0
GoutGout
Alexa Carlson, PharmD, BCPS
Northeastern University
1. Define and explain commonly used medical terminology and abbreviations within the
context of a patient case.
2. Describ...
Neogi T. Gout. N Engl J Med. 2011:364(5):443-452.
Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheu...
Gout is the most common cause of inflammatory
arthritis in the US
Substantial gaps in the management of gout
Significant l...
Hyperuricemia: elevated serum uric acid
Tophus: a calculus containing sodium urate that
develops around fibrous tissue aro...
Elevated serum uric acid (SUA)
>7mg/dL (416μmol/L) at 37°C for men
>6mg/dL (357μmol/L) at 37°C for women
Considered to be ...
Clinical spectrum of disease:
Hyperuricemia
Recurrent acute arthritis
attacks due to monosodium
urate (MSU) crystals in sy...
“Disease of Kings”
Alexander the Great
King Henry VIII
Benjamin Franklin
Alexander Hamilton
Voltaire
Health.com List of 8 ...
Increasing prevalence of gout
Developed Countries > Developing Countries
3.9% of adults in the US (~8.3 million people)
$3...
Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved.
Purine metabolism. (HGPRT, hypoxant...
Uric acid is the end product of purine metabolism
Elevated uric acid can occur from over-production or
under-excretion of uric acid
Over-production:
Less common
Genetic abn...
Image from: www.goutrx.com
A. All patients with gout with progress to chronic
tophaceous gout
B. All patients with gout have hyperuricemia
C. Patient...
Increasing age
Sex (Male > Female)
Hyperuricemia
Obesity
High Blood Pressure
Injury
Fasting
Recent surgery
Foods/Drinks
Me...
Foods high in purines
Foods and drinks with high fructose corn
syrup
Alcohol
Picture taken from: aldrodriguezliverfoundati...
Diuretics (thiazide
and loop diuretics)
Cyclosporine and
tacrolimus
Low dose salicylates
(<2g/day)
Levodopa
Pyrazinamide
C...
Chronic renal insufficiency
Hypothyroidism
Renal Transplant
Hypertension
Coronary heart disease
Myeloproliferative disorde...
RT is a 48 year old male
PMH: HTN, Type II DM, CHF
SH: 5 pack-year history, drinks 2 beers per night
Current Medications: ...
A. One
B. Two
C. Three
D. Four
Symptoms:Symptoms:
•Rapid onsetRapid onset
•Over night or after a trigger (alcohol,Over night or after a trigger (alcohol,...
http://knol.google.com/k/gout
• Differential Diagnosis:
– Pseudogout (calcium pyrophosphate crystals)
– Septic arthritis
– Rheumatoid arthritis
– Trauma...
Zhang W, Doherty M, Pascual E, et al. EULAR Evidence Based Recommendations for Gout. Part I: Diagnosis. Report of a Task F...
• Level A: Supported by multiple (ie, more than
one) randomized clinical trials or meta-analyses
• Level B: Derived from a...
Colchicine,Colchicine,
NSAIDs,NSAIDs,
CorticosteroidsCorticosteroids
http://rwglobal.com/~slpm/tipe/p
ictures/gout.jpg
• Acute flares are self-limiting
• Treatment objective is rapid relief of symptoms
• All therapy should be initiated withi...
Ann Rheum Dis. 2006;65:1312-24.
• Mechanism of Action: Peripheral inhibition of
COX leading to inhibition of prostaglandin
synthesis
• Dosing:
NSAID Typic...
• Adverse Effects: increased BP, sodium and
water retention, gastritis, GI bleeding
• Contraindications/Precautions:
Ann R...
• FDA-Approved: indomethacin, naproxen,
sulindac
• NO NSAID has been shown to be superior to
another
• Role in Therapy:
– ...
• Mechanism of Action: anti-inflammatory
• Dosing:
Corticosteroid Typical Regimen
Prednisone 0.5 mg/kg/day x5-10d, then st...
• Adverse Effects: hyperglycemia, leukocytosis,
fluid retention, impaired wound healing, GI
upset, insomnia
• Precautions:...
Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a
Double-Blind, Randomized Equivalence Trial
Met...
Janssens HJEM, Janssen M, van de Lisdonk EH, et al. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthrit...
• Mechanism of Action:
– May interfere with the intracellular assembly of the
inflammasome complex present in neutrophils ...
Methods Multicenter, randomized, double-blind, placebo-
controlled, parallel-group study
Treatment Arms
(n=184)
Placebo (n...
• Acute Flare:
– FDA Approved: 1.2mg po at sign of first flare,
followed in 1 hour with a single dose of 0.6mg (max
of 1.8...
• Prophylaxis:
– No adjustments for mild-moderate renal impairment
– Dose adjust to 0.3mg po daily in severe renal impairm...
• Prophylaxis:
– No dose adjustment needed for mild-moderate
hepatic impairment
– Consideration to dose adjustment for sev...
• Adverse Effects:
– GI: Diarrhea, nausea, vomiting, abdominal
cramping/pain
– Blood dyscrasias: myelosupression, leukopen...
• Drug Interactions: Substrate of CYP3A4, PGP;
Induces CYP2C8, 2C9, 2E1, 3A4
– 3A4 Inhibitors
– PGP Inhibitors
– HMG Co-A ...
Colcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012.
Requires dose adjustmentsRequires dose adjustments
i...
• Role in Therapy:
– FIRST LINE agent for acute gouty attacks w/in 36h
of attack (Evidence A)
– FIRST LINE prophylaxis in ...
• MOA:
– Anakinra: Competitively inhibits IL-1 from binding to
the IL-1 type 1 receptors
– Canakinumab: Recombinant IL-1β ...
Medication BSR EULAR ACR
Nonsteroidal
Anti-
inflammatory
Drugs (NSAIDs)
First line First Line First Line
Corticosteroid Ef...
• Comorbid conditions
• Effectiveness of past
treatments
• Patient preference
• Joint involvement
• Severity
• Duration of...
Severity of Acute Gouty Arthritis Attack (based on 0-10 visual
analog scale)
Mild ≤4
Moderate 5-6
Severe ≥7
Duration of th...
Extent of acute gouty arthritis attack
One or a few small joints
1-2 large joints (ankle, knee, writs, elbow, hip, shoulde...
Adequate Response:Adequate Response:
•>20% improvement in>20% improvement in
pain score w/in 24hpain score w/in 24h
•≥50% ...
Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved.
Algorithm for management of an acut...
Disease State Considerations for Selection of Acute Gout
Therapy
CKD NSAIDs, COX-2 Inhibitors, Colchicine
CHF NSAIDs, COX-...
• Self-limiting disease; ~7-10 days of treatment usually
required
• Colchicine/NSAIDs/Corticosteroids are all first line
•...
RT is a 48 year old male with PMH significant for
HTN, Type II DM, CHF
Patient presented to the emergency room with a 12
h...
A. Naproxen 500mg po BID
B. Colchicine 1.2mg po once, then 0.6mg po one
hour later
C. Prednisone 30mg po daily
A. Naproxen 500mg po BID
B. Colchicine 1.2mg po once, then 0.6mg po one
hour later
C. Prednisone 30mg po daily
D. Intra-ar...
• Presentation:
– Tophus: urate deposits
– Fingers>olecranon bursae>forearm>achilles
tendon>knees>wrists>hand
• Late compl...
Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
Upon discussion with RT in the ER, the physician
discovers this is the third exacerbation RT has had
this year.
Is RT indi...
LOW DOSELOW DOSE
Colchicine, NSAIDs,Colchicine, NSAIDs,
CorticosteroidsCorticosteroids
Image from: www.goutrx.com
Methods Randomized, prospective, double-blind, placebo controlled trial
Treatment Arms
(n=43)
Colchicine 0.6 mg po BID (n=...
• First Line: Colchicine or low dose NSAIDs
– Colchicine 0.6mg po daily or BID
– Low Dose NSAIDS (i.e. Naproxen 250mg po B...
Figure 5 from Arthritis Care & Research. 2012;64(10):1457.
Signs/Symptoms of Gout:Signs/Symptoms of Gout:
acute gouty arth...
RT is a 48 year old male with PMH significant for
HTN, Type II DM, CHF
Patient presented to the emergency room with a 12
h...
What prophylactic therapy would you want to use
in RT and why?
A. Colchicine
B. Naproxen
C. Prednisone
Allopurinol,Allopurinol,
Febuxostat,Febuxostat,
Probenecid,Probenecid,
Pegloticase…Pegloticase…
• Mechanism of Action: Competitively inhibits the
postsecretory renal proximal tubular
reabsorption of uric acid
• Dose:
•...
• Adverse Effects:
– Cardiovascular: Flushing
– CNS: Dizziness, fever, headache
– Dermatologic: Alopecia, dermatitis, prur...
• Contraindication: History of urolithiasis,
overproducers of uric acid, hypersensitivity to
probenecid, small or large do...
• Drug Interactions:
– Salicylates
– Penicillins/cephalosporins/carbapenems
– Methotrexate
– Pegloticase
• Monitoring: ser...
• Place in Therapy:
– “ALTERNATIVE” FIRST LINE therapy to xanthine
oxidase inhibitors (XOI)
– May be used in conjunction w...
• If patient has HTN or hyperlipidemia consider the
use of losartan and fenofibrate
• Both have uricosuric properties
• Pl...
• Mechanism of Action: Xanthine Oxidase inhibitor
which causes reduced uric acid production
• Dosing: Start at 50-100mg po...
Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not
Provide Adequate Control of Hyperuricemia in Pat...
Group SUA Number of patients achieving
SUA ≤6mg/dL (0.36mmol/L)
No allopurinol 0.57 mmol/L 1/23 (4%)
Lower than
recommende...
Dalbeth N, Kumar S, Stamp L et al. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequ...
• Renal:
– Initiation of Therapy:
• 50mg for people with CKD stage ≥ 4
• 100mg for everyone else
– Chronic Therapy:
• “Dos...
• Adverse Effects:
– Dermatologic: Rash (<1%), Allopurinol hypersensitivity
syndrome (AHS)
– Hematologic: agranulocytosis,...
• Monitoring: SUA every few weeks initially, HLA-
B*5801 prior to initiation in high risk
subpopulations (Koreans with sta...
• MOA: non-purine inhibitor of xanthine oxidase
(XO)
• Dosage:
– Initiate at 40mg po daily; if goal SUA is not
achieved by...
• Adverse Effects:
– Hepatic: abnormal LFTs
– GI: nausea
– Rheumatologic: Gout flares due to mobilization
– Others: arthra...
• Precaution:
– Acute gout flare
– Cardiovascular events
– Hepatotoxicity
• Drug-Interactions: azathioprine/6-
mercaptouri...
• Monitoring: SUA after 2 weeks of treatment;
LFTs at baseline and repeated if signs of hepatic
injury
• Place in Therapy:...
Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout.
Methods Randomized, multi-center, double-bli...
Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout.
Results • Percentage of patients with SUA <6...
• MOA: pegylated recombinant modified
mammalian urate oxidase (uricase)
• Dose: 8mg IV infusion over 2 hours Q2 weeks;
wit...
• Adverse Effects: Gout flares, infusion reactions,
nausea, vomiting, bruising, nasopharyngitis,
constipation, chest pain,...
• Precautions:
– Anaphylaxis: Most often occurs within 2 hours of
the infusion; pre-medicate patients and observe
them
– I...
• Drug Interactions: No studies of pegloticase with other
drugs have been conducted
• Monitor: SUA levels, G6PD screening ...
XO inhibitors: allopurinol, febuxostat
XO inhibitors: allopurinol, febuxostat
Uricosurics: probenecid, losartan,
fenofibra...
BSR EULAR ACR
Goals of
Therapy
≤ 5mg/dL ≤ 6mg/dL ≤6 mg/dL, and often ≤5
mg/dL
Prophylaxis
for Acute
Gout
Colchicine for up...
BSR EULAR ACR
Allopurinol Drug of choice;
Initial treatment
starting at 50-
100mg/day and
adjusted for renal
function if
n...
• Historically, we do not initiate urate lowering
therapy during the acute attack due to risk of
worsening the attack
• Ne...
Figure 3 from Arthritis Care & Research. 2012;64(10):1437.
Long TermLong Term
Monitoring:Monitoring:
•SUA Q2-5SUA Q2-5
wee...
Table 4 from Arthritis Care & Research. 2012;64(10):1441.
• Unclear etiology of hyperuricemia
• Refractory signs/symptoms of gout
• Difficult to control and reach target SUA
• Mult...
• Patient should be started on prophylaxis (low dose colchicine,
NSAID, prednisone) just prior to or with the start of ULT...
These are being performed at the sameThese are being performed at the same
time. We look to see if they need ULT,time. We ...
Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved.
Algorithm for management of hyperur...
Upon discussion with RT in the ER, the physician
discovers this is the third exacerbation RT has had
this year. He has onl...
What Urate Lowering Therapy would you want to
start in RT, and why?
A. Allopurinol
B. Febuxostat
C. Probenecid
D. Nothing
When would you want to start urate lowering
therapy in RT?
A.Immediately, he is already on prophylactic
therapy
B.After he...
• Should always be considered alone or in
combination with pharmacologic therapy
• Smoking cessation
• Patient Education
•...
Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
Avoid Limit Encourage
• Organ Meats high in purine
(eg, sweetbreads, liver,
kidney)
• Serving Sizes of:
• Beef, lamb, pork...
Given the following patient case, identify the
options for non-pharmacologic treatment of
gout:
• RT is 6’4” and 240lbs
• ...
• RT is 6’4” and 240lbs
• Current Medications: metoprolol XL 50mg po
daily, aspirin 81mg po daily, lisinopril 20mg po
dail...
• Royal Pains: Season 2 Episode 10 (available on
Netflix)
– 13:20-14:33
– 28:37-29:45
– 33:25-35
• What would be in your differential diagnosis for
this patient?
• What signs/symptoms of gout does this patient
present w...
A.Treatment plan is appropriate
B. Treatment plan is inappropriate
A. Start the allopurinol as planned.
B. Treat the acute attack, then start allopurinol
C. Treat the acute attack, then sta...
• Acute
– Non-Pharmacologic: rest, ice
– Pharmacologic:
• NSAIDs, colchicine, corticosteroids to treat (~7-10 day)
• CONTI...
• Chronic
– Non-Pharmacologic: diet, fluids,
weight loss, smoking cessation,
avoidance of risk factors
– Pharmacologic:
• ...
• We probably wont have time to work on these
during class, but Elizabeth Akselrod, PharmD
Class of 2015, and I made some ...
1. Which of the following is the goal of urate
lowering therapy?
A. SUA <6mg/dL
B. SUA <4 mg/dL
C. SUA <7mg/dL
D. Lower th...
3) There is new evidence to support dosing
allopurinol to a target serum uric acid, instead of
renal dose adjustment
a) Tr...
5) Patients being treated for gout should receive
pharmacologic treatment only
a) True
b) False
6) When initiating urate l...
• MC is a 21 yoF who presents to her PCP for an annual checkup. Her parents have
been concerned because lately she hasn’t ...
• RW (prefers to be called Fat Amy) is a 28 yoF who was shooting a film in Hollywood when all of a
sudden she felt pain in...
• TS is a 59 yoM who presents to the ER for the 4th
time this year with an acute
gouty attack. He rates his pain as a 6/10...
• SN is a 63 yoM who has no significant PMH except has been taking Allopurinol 300
mg PO daily for 1 year due to frequent ...
• HR is a 45 yoF who has had breakthrough gouty
attacks despite Allopurinol treatment. Her PMH
is significant for HTN, DMT...
• Dr. Sampson is a new resident and wants to start
a patient on Allopurinol for chronic gout
treatment. He asks you for he...
• TY comes into your pharmacy to pick up his newly
prescribed probenecid. He has never heard of this
medication and knows ...
• RC 67 year old African American male comes is a
regular patient at your pharmacy. His past
medical history includes Hype...
Colcrys 1.2mg po once followed by
0.6mg 1 hour later, then 12 hours
later start 0.6mg po BID x 7 days.
RC 67
7/6/14
Gout cdm2 2014_class version(1)
Gout cdm2 2014_class version(1)
Gout cdm2 2014_class version(1)
Gout cdm2 2014_class version(1)
Gout cdm2 2014_class version(1)
Gout cdm2 2014_class version(1)
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Gout for pharmacists; class version

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  • HANDOUT:
    In PI there is a table for the potent v moderate and the p-glycoprotein and hepatic renal insufficiency and how to doseFIND THIS AND PUT IT IN THERE
    Colcrys (colchicine) is a substrate of the efflux transporter PGP. Of the CYP450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colcrys is administered with drugs that inhibit PGP, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.
  • Colchicine decreases the average number of gout flares, decreases the likelihood of having one or multiple acute flares, and decreases the severity of flares. No change in the length of gout flares.
    The benefits was observed overall, from 0 to 3 months, and from 3 to 6 months.
    A significant difference persisted in those subjects continuing colchicine for up to 6 months total
    Colchicine
    Placebo
    P-value
    Acute Gout Flares
    33% of patients
    77% of patients
    0.008
    Multiple Gout Flares
    14% of patients
    63% of patients
    0.004
    Visual Analog Scale
    3.64
    5.08
    0.018
    Length of Acute Gout Flares
    6 days
    5.56 days
    0.566
  • We would start ppx as we
  • Transcript of "Gout cdm2 2014_class version(1)"

    1. 1. GoutGout Alexa Carlson, PharmD, BCPS Northeastern University
    2. 2. 1. Define and explain commonly used medical terminology and abbreviations within the context of a patient case. 2. Describe and correlate signs and symptoms, epidemiology, risk factors, pathogenesis, natural history of disease, clinical course, etiology, and prevention and treatment of commonly encountered diseases. 3. Apply scientific knowledge and principles of medicinal chemistry, pharmacology, pharmaceutics, pharmacogenomics and pharmacokinetics to the design of rational therapeutic strategies 4. Identify evidence based, patient specific therapeutic goals and outcome measures for a patient started on a drug therapy regimen. 5. Apply evidenced based medicine to compare and contrast therapeutic options for a given medical problem and/or disease state in terms of safety, efficacy (including clinical evidence), ease of administration, cost, and other patient specific factors. 6. Design and defend a patient-specific therapeutic regimen, which is safe, efficacious and practical. For each drug selected, include drug name (generic and brand) dose, route, frequency and time of administration, and duration of therapy when applicable. 7. Predict the influence of selected drugs on a patient’s other diseases or problems and outline which agents should be avoided or monitored more carefully.
    3. 3. Neogi T. Gout. N Engl J Med. 2011:364(5):443-452. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care & Research. 2012:64(10);1431-1446. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 2: Therapy and Antiinflammatory Prophylaxis of Acute Gouty Arthritis. Arthritis Care & Research. 2012:64(10);1447- 1461. Jordan DM, Cameron JS, Snaith M, et al. British Society for Rheumatology Guideline for the Management of Gout. Rheumatology. 2007;46:1372-1374. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Report of a task force of the standing committee for international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis. 2006l65:1301-1311. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1312-1324. Roddy E, Zhang W, Doherty M. Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations. Ann Rheum Dis. 2007;66:1311-1315.
    4. 4. Gout is the most common cause of inflammatory arthritis in the US Substantial gaps in the management of gout Significant lack of patient education and adherence to management
    5. 5. Hyperuricemia: elevated serum uric acid Tophus: a calculus containing sodium urate that develops around fibrous tissue around joints, typically in patients with gout Podagra: a painful condition of the big toe caused by gout Uricase: An enzyme that oxidatively degrade uric acid, thereby catalyzing conversion to soluble allantoin, which is much more soluble than uric acid. This enzyme is found in most animals, but not in humans. Uricosuric medications: Medications administered to increase the elimination of uric acid.
    6. 6. Elevated serum uric acid (SUA) >7mg/dL (416μmol/L) at 37°C for men >6mg/dL (357μmol/L) at 37°C for women Considered to be the principle cause of gouty arthritis Not all patients with hyperuricemia develop acute gout flares or chronic gouty complications
    7. 7. Clinical spectrum of disease: Hyperuricemia Recurrent acute arthritis attacks due to monosodium urate (MSU) crystals in synovial fluid Deposition of MSU into articular and extra-articular space (tophi) Interstitial renal disease Uric acid nephrolithiasis Primarily caused by elevated SUA levels, but can occur in patients with normal SUA levels. http://www.healthinplainenglish.com/health /musculoskeletal/gout/ http://www.assh.org/Public/HandConditions/Pag es/GoutandPseudogout.aspx
    8. 8. “Disease of Kings” Alexander the Great King Henry VIII Benjamin Franklin Alexander Hamilton Voltaire Health.com List of 8 people with gout: http://www.health.com/health/gallery/0,,2045 1892,00.html Image from: antabusediaries.blogspot.com
    9. 9. Increasing prevalence of gout Developed Countries > Developing Countries 3.9% of adults in the US (~8.3 million people) $3.9 million in annual physician visits Richette P, Bardin T. Gout. Lancet. 2010;375:318-28.
    10. 10. Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved. Purine metabolism. (HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate.) Legend: From: Chapter 74. Gout and Hyperuricemia Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
    11. 11. Uric acid is the end product of purine metabolism
    12. 12. Elevated uric acid can occur from over-production or under-excretion of uric acid Over-production: Less common Genetic abnormalities in enzymes related purine metabolism Increased phosphoribosyl pyrophosphate synthetase (PRPP) Decreased hypoxanthine-guanine phosphoribosylthransferase (HGPRT) Increased cell turnover (cytotoxic chemotherapy, malignancies) Under-excretion: More common (~90%) Decline in urinary excretion of uric acid Can determine by measuring urine uric acid >600mg/24h over-production <600mg/24h under-excretion
    13. 13. Image from: www.goutrx.com
    14. 14. A. All patients with gout with progress to chronic tophaceous gout B. All patients with gout have hyperuricemia C. Patients with gout will have recurrent acute attacks separated by intercritical periods D. Gout is primarily due to the overproduction of uric acid
    15. 15. Increasing age Sex (Male > Female) Hyperuricemia Obesity High Blood Pressure Injury Fasting Recent surgery Foods/Drinks Medications Medical Conditions Genetics
    16. 16. Foods high in purines Foods and drinks with high fructose corn syrup Alcohol Picture taken from: aldrodriguezliverfoundation.com
    17. 17. Diuretics (thiazide and loop diuretics) Cyclosporine and tacrolimus Low dose salicylates (<2g/day) Levodopa Pyrazinamide Cytotoxic chemotherapy Cyclosporine Nicotinic Acid (Niacin) Ethambutol
    18. 18. Chronic renal insufficiency Hypothyroidism Renal Transplant Hypertension Coronary heart disease Myeloproliferative disorders Lymphoproliferative disorders Lead toxicity Starvation Acromegaly Down’s syndrome Hypoxanthine-guanine phosphoribosyltransferase deficiency Diabetes mellitus Volume depletion Ketoacidosis Lactic Acidosis Hyper/Hypo-parathyroidism Sarcoidosis Preeclampsia Starvation Heart Failure Acute alcoholism Phosphoribosylpyrophosphate synthetase overactivity Pernicious anemia Psoriasis
    19. 19. RT is a 48 year old male PMH: HTN, Type II DM, CHF SH: 5 pack-year history, drinks 2 beers per night Current Medications: metoprolol XL 50mg po daily, aspirin 81mg po daily, lisinopril 20mg po daily, metformin 1000mg po BID, furosemide 40mg po daily
    20. 20. A. One B. Two C. Three D. Four
    21. 21. Symptoms:Symptoms: •Rapid onsetRapid onset •Over night or after a trigger (alcohol,Over night or after a trigger (alcohol, meats, diuretics)meats, diuretics) •Excruciating painExcruciating pain Signs:Signs: •Monoarticular arthritis early on (mayMonoarticular arthritis early on (may become polyarticular in late gout)become polyarticular in late gout) •Often occurs in a joint in the lowerOften occurs in a joint in the lower extremityextremity •Redness/Swelling/Inflammation/WarmtRedness/Swelling/Inflammation/Warmt h of the jointh of the joint •FeverFever •Elevated serum uric acid leukocytosisElevated serum uric acid leukocytosis •Monosodium urate cyrstals in synovialMonosodium urate cyrstals in synovial fluidfluid
    22. 22. http://knol.google.com/k/gout
    23. 23. • Differential Diagnosis: – Pseudogout (calcium pyrophosphate crystals) – Septic arthritis – Rheumatoid arthritis – Trauma • Diagnosis: – Evidence of monosodium urate (MSU) crystals by joint aspiration is gold standard for definitive diagnosis – Often made on as a clinical diagnosis
    24. 24. Zhang W, Doherty M, Pascual E, et al. EULAR Evidence Based Recommendations for Gout. Part I: Diagnosis. Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.
    25. 25. • Level A: Supported by multiple (ie, more than one) randomized clinical trials or meta-analyses • Level B: Derived from a single randomized trial, or nonrandomized studies • Level C: Consensus opinion of experts, case studies, or standard-of-care
    26. 26. Colchicine,Colchicine, NSAIDs,NSAIDs, CorticosteroidsCorticosteroids
    27. 27. http://rwglobal.com/~slpm/tipe/p ictures/gout.jpg
    28. 28. • Acute flares are self-limiting • Treatment objective is rapid relief of symptoms • All therapy should be initiated within 24h of gout symptom onset and continued for 1-2 weeks • Do NOT discontinue urate lowering therapy in an acute attack Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    29. 29. Ann Rheum Dis. 2006;65:1312-24.
    30. 30. • Mechanism of Action: Peripheral inhibition of COX leading to inhibition of prostaglandin synthesis • Dosing: NSAID Typical Regimen Etodolac 300mg Q12h Fenoprofen 300-600mg Q6-8h Ibuprofen 800mg Q6h Indomethacin 25-50mg Q6h x 3d, then taper to Q12h x 4-7d Ketoprofen 75mg Q6h Naproxen 500mg Q12h x 3d, then 250-500mg daily x 4-7d Piroxicam 20mg daily or divided Q12h Sulindac 200mg Q12h x 7-10d
    31. 31. • Adverse Effects: increased BP, sodium and water retention, gastritis, GI bleeding • Contraindications/Precautions: Ann Rheum Dis. 2006:65:;312-24. NEJM. 2011:364(5);443-452.
    32. 32. • FDA-Approved: indomethacin, naproxen, sulindac • NO NSAID has been shown to be superior to another • Role in Therapy: – FIRST LINE for acute gouty attacks w/o contraindication at high doses FIRST LINE alternative option to colchicine for prophylaxis
    33. 33. • Mechanism of Action: anti-inflammatory • Dosing: Corticosteroid Typical Regimen Prednisone 0.5 mg/kg/day x5-10d, then stop (Evidence A) <OR> 0.5mg/kg/day x2-5d, then taper for 7-10d, then stop (Evidence C) Methylprednisolone Methylprednisolone oral dose pack (Evidence C) Methylprednisolone IM 100-150mg daily x1-2d Triamcinolone IM 60mg once, then oral prednisone (Evidence C) Triamcinolone intra-articular 10-40mg (large joints) or 5-20mg (small joints) once (Evidence B)
    34. 34. • Adverse Effects: hyperglycemia, leukocytosis, fluid retention, impaired wound healing, GI upset, insomnia • Precautions: Infection, DM, peptic ulcer disease • Role in Therapy: – FIRST LINE therapy in acute gout – Consider intra-articular corticosteroids in patients with gout affecting 1-2 large joints – SECOND LINE therapy in prophylaxis to NSAIDs and colchicineJanssens HJEM, Janssen M, van de Lisdonk EH, et al. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a Double-Blind, Randomized Equivalence Trial. Lancet. 2008;371:1854-60.
    35. 35. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a Double-Blind, Randomized Equivalence Trial Methods Randomized, double-blind, double-dummy, active-comparator, controlled trial in monoarticular gout to assess equivalency Intervention • Naproxen 500mg po BID x 5 days (n=59) • Prednisolone 35mg po daily x 5 days (n=59) Primary Outcomes Pain in the affected joint measured by the 100mm visual analogue scale Results Reduction in mean pain score on visual analogue scale on day 4: •44.7mm prednisolone •46mm naproxen •Difference 1.3mm (95% CI -9.8-7.1) Relief of symptoms on day 4: •Clinically significant improvements: 80% prednisolone and 87% naproxen patients •Complete relief of symptoms: 22% prednisolone and 17% naproxen patients Janssens HJEM, Janssen M, van de Lisdonk EH, et al. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a Double-Blind, Randomized Equivalence Trial. Lancet. 2008;371:1854-60.
    36. 36. Janssens HJEM, Janssen M, van de Lisdonk EH, et al. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a Double-Blind, Randomized Equivalence Trial. Lancet. 2008;371:1854-60. Janssens HJEM, Janssen M, van de Lisdonk EH, et al. Use of Oral Prednisolone or Naproxen for the Treatment of Gout Arthritis: a Double-Blind, Randomized Equivalence Trial. Lancet. 2008;371:1854-60.
    37. 37. • Mechanism of Action: – May interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates the activation of interlukin-1β – Disruption of cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules which prevents the activation, degranulation, and migration of neutrophils Colcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012.
    38. 38. Methods Multicenter, randomized, double-blind, placebo- controlled, parallel-group study Treatment Arms (n=184) Placebo (n=59) Low-dose colchicine (1.2 mg po with 0.6 mg in 1 hour (1.8 mg total)) (n=74 ) High-dose colchicine (1.2 mg po followed by 0.6 mg every hour for 6 hours (4.8 mg total)) (n=52) Primary Outcome ≥50% pain reduction at 24 hours without rescue medication Results Low and high-dose colchicine were significantly superior to placebo in reduction of pain at 24 hours (p=0.005, 0.034 respectively) Overall adverse event rates for high-dose, low-dose, and placebo groups were 76.9%, 36.5%, and 27.1% respectively Terkeltaub RA, Furst DE, Bennett K, et al. High Versus Low Dosing of Oral Colchicine for Early Acute Gout Flare. Arthritis Rheum. 2010;62(4):1060-68.
    39. 39. • Acute Flare: – FDA Approved: 1.2mg po at sign of first flare, followed in 1 hour with a single dose of 0.6mg (max of 1.8mg) – Real Life: FDA Approved dose (1.8mg total) then 12 hours later start prophylaxis dosing (0.6mg po daily or BID) until the end of the gouty attack. • Prophylaxis: 0.6mg po once or twice daily (max 1.2mg daily) Arthritis Care Res. 2012:64(10);1454.
    40. 40. • Prophylaxis: – No adjustments for mild-moderate renal impairment – Dose adjust to 0.3mg po daily in severe renal impairment – In patients on HD, the dose is 0.3mg po twice weekly • Treatment: – No dose adjustments for mild-severe renal impairment – For severe renal impairment, treatment courses should not be repeated more than once every 2 weeks – In patients on HD, the dose is 0.6mg po once, and treatment courses should not be repeated more than once every 2 weeks
    41. 41. • Prophylaxis: – No dose adjustment needed for mild-moderate hepatic impairment – Consideration to dose adjustment for severe hepatic impairment • Treatment: – No dose adjustment needed for mild-severe hepatic impairment – In patients with severe hepatic impairment, treatment courses should not be repeated more than once every 2 weeks
    42. 42. • Adverse Effects: – GI: Diarrhea, nausea, vomiting, abdominal cramping/pain – Blood dyscrasias: myelosupression, leukopenia, granulocytopenia, thrombocytopenia, aplastic anemia – Neuromuscular Toxicity: myopathy, rhabdomyolysis, muscle weakness/pain • Contraindication: patients with renal or hepatic impairment should not use colchicine with a p- glycoprotein (PGP) or strong CYP3A4 inhibitorColcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012.
    43. 43. • Drug Interactions: Substrate of CYP3A4, PGP; Induces CYP2C8, 2C9, 2E1, 3A4 – 3A4 Inhibitors – PGP Inhibitors – HMG Co-A Reductase Inhibitors, fibrates Colcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012.
    44. 44. Colcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012. Requires dose adjustmentsRequires dose adjustments if currently on these meds,if currently on these meds, or if recently (w/in the pastor if recently (w/in the past 14 days) on the meds listed14 days) on the meds listed
    45. 45. • Role in Therapy: – FIRST LINE agent for acute gouty attacks w/in 36h of attack (Evidence A) – FIRST LINE prophylaxis in patients initiated on urate lowering therapy for up to 6 months (Evidence A) • Cost: 0.6mg (30 tablets) $196.15 Colcrys [package insert]. Philadelphia, PA: AR Scientific, Inc; 2012.
    46. 46. • MOA: – Anakinra: Competitively inhibits IL-1 from binding to the IL-1 type 1 receptors – Canakinumab: Recombinant IL-1β monoclonal antibody • Dose: – Anakinra: 100mg SQ daily x 3 days – Canakinumab: 150mg SQ once • Role in Therapy: – Canakinumab is approved in the EU for acute gout – FDA has not approved either in America for gout
    47. 47. Medication BSR EULAR ACR Nonsteroidal Anti- inflammatory Drugs (NSAIDs) First line First Line First Line Corticosteroid Effective Alternative Effective Alternative First Line Colchicine Effective Alternative First line First Line w/in 36h on attack onset British Society for Rheumatology (BSR), European League Against Rheumatism (EULAR), American College of Rheumatology (ACR) Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    48. 48. • Comorbid conditions • Effectiveness of past treatments • Patient preference • Joint involvement • Severity • Duration of attack • Concomitant medications
    49. 49. Severity of Acute Gouty Arthritis Attack (based on 0-10 visual analog scale) Mild ≤4 Moderate 5-6 Severe ≥7 Duration of the gouty arthritis attack since onset Early <12h after attack onset Well-Established 12-36h after attack onset Late >36h after attack onset Arthritis Care Res. 2012:64(10);1451.
    50. 50. Extent of acute gouty arthritis attack One or a few small joints 1-2 large joints (ankle, knee, writs, elbow, hip, shoulder) Polyarticular: • ≥4 joints w/arthritis involving more than 1 region (forefoot, midfoot, ankle/hindfoot, knee, hip, fingers, wrist, elbow, shoulder, other) • Acute gout attack involving 3 separate large joints Arthritis Care Res. 2012:64(10);1451.
    51. 51. Adequate Response:Adequate Response: •>20% improvement in>20% improvement in pain score w/in 24hpain score w/in 24h •≥50% improvement in50% improvement in pain scorepain score ≥ 24h24h Adequate Response:Adequate Response: •>20% improvement in>20% improvement in pain score w/in 24hpain score w/in 24h •≥50% improvement in50% improvement in pain scorepain score ≥ 24h24h Combination Therapy:Combination Therapy: (1)(1)NSAID + colchicineNSAID + colchicine (2)(2)Corticosteroids +Corticosteroids + colchicinecolchicine (3)(3)Intra-articular steroidsIntra-articular steroids + anything+ anything Combination Therapy:Combination Therapy: (1)(1)NSAID + colchicineNSAID + colchicine (2)(2)Corticosteroids +Corticosteroids + colchicinecolchicine (3)(3)Intra-articular steroidsIntra-articular steroids + anything+ anything Figure 3 from Arthritis Care Res. 2012:64(10);1452.
    52. 52. Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved. Algorithm for management of an acute gout attack. Legend: From: Chapter 74. Gout and Hyperuricemia Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014 From: Chapter 74. Gout and Hyperuricemia Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
    53. 53. Disease State Considerations for Selection of Acute Gout Therapy CKD NSAIDs, COX-2 Inhibitors, Colchicine CHF NSAIDs, COX-2 Inhibitors, Corticosteroids Peptic Ulcer Disease NSAIDs, COX-2 Inhibitors, Corticosteroids Anticoagulation/ Antiplatelet Therapy NSAIDs Diabetes Corticosteroids Infection or Infection Risk Corticosteroids Hepatic Disease NSAIDs, COX-2 Inhibitors, Colchicine
    54. 54. • Self-limiting disease; ~7-10 days of treatment usually required • Colchicine/NSAIDs/Corticosteroids are all first line • Select the agent based on insurance/joint involvement/pain severity/co-morbid conditions/concomitant medications/duration of attack • Appropriate response is a 50% reduction in pain in 24h • If a patient is on urate lowering therapy, it should not be stopped during the acute attack
    55. 55. RT is a 48 year old male with PMH significant for HTN, Type II DM, CHF Patient presented to the emergency room with a 12 hour history of acute tenderness, and redness of his left big toe. Pain Score: 4/10 on visual analog scale BP 178/92 mmHg in ER 145 105 22 1263.8 250
    56. 56. A. Naproxen 500mg po BID B. Colchicine 1.2mg po once, then 0.6mg po one hour later C. Prednisone 30mg po daily
    57. 57. A. Naproxen 500mg po BID B. Colchicine 1.2mg po once, then 0.6mg po one hour later C. Prednisone 30mg po daily D. Intra-articular steroids
    58. 58. • Presentation: – Tophus: urate deposits – Fingers>olecranon bursae>forearm>achilles tendon>knees>wrists>hand • Late complication of gout, uncommon in the general population • Complications: – Joint deformities and destruction – Pain – Damage to surrounding tissue
    59. 59. Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    60. 60. Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    61. 61. Upon discussion with RT in the ER, the physician discovers this is the third exacerbation RT has had this year. Is RT indicated for urate lowering therapy? A. Yes A. No
    62. 62. LOW DOSELOW DOSE Colchicine, NSAIDs,Colchicine, NSAIDs, CorticosteroidsCorticosteroids
    63. 63. Image from: www.goutrx.com
    64. 64. Methods Randomized, prospective, double-blind, placebo controlled trial Treatment Arms (n=43) Colchicine 0.6 mg po BID (n=21) Placebo po BID (n=22) Primary Outcome Number of gout flares during the initiation of allopurinol Results Reduction in the number pts with acute gout flares (33% of colchicine pts versus 77% placebo pts (p=0.008)) Reduction in the number of pts with multiple gout flares (14% of colchicine pts vs 63% placebo pts (p=0.004)) Borstad GC, Bryant LR, Abel MP, et al. Colchicine for Prophylaxis of Acute Flares When Initiating Allopurinol for Chronic Gouty Arthritis. J Rheumatol. 2004;31(12):2429-32.
    65. 65. • First Line: Colchicine or low dose NSAIDs – Colchicine 0.6mg po daily or BID – Low Dose NSAIDS (i.e. Naproxen 250mg po BID) • Second Line: Corticosteroids – Prednisone or prednisolone ≤10 po mg/day • Role: Initiated just prior to/at start of urate lowering therapy to prevent acute gouty attacks Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446. Keep in mind toKeep in mind to check the need forcheck the need for GI prophylaxis withGI prophylaxis with long term NSAIDslong term NSAIDs
    66. 66. Figure 5 from Arthritis Care & Research. 2012;64(10):1457. Signs/Symptoms of Gout:Signs/Symptoms of Gout: acute gouty arthritis in theacute gouty arthritis in the past 3 months, presence ofpast 3 months, presence of palpable tophus or tophi,palpable tophus or tophi, chronic tophaceous goutychronic tophaceous gouty arthropathy (with chronicarthropathy (with chronic synovitis) in the past 3synovitis) in the past 3 monthsmonths
    67. 67. RT is a 48 year old male with PMH significant for HTN, Type II DM, CHF Patient presented to the emergency room with a 12 hour history of acute tenderness, and redness of his left big toe. Pain Score: 4/10 on visual analog scale BP 178/92 mmHg in ER 145 105 22 1263.8 250
    68. 68. What prophylactic therapy would you want to use in RT and why? A. Colchicine B. Naproxen C. Prednisone
    69. 69. Allopurinol,Allopurinol, Febuxostat,Febuxostat, Probenecid,Probenecid, Pegloticase…Pegloticase…
    70. 70. • Mechanism of Action: Competitively inhibits the postsecretory renal proximal tubular reabsorption of uric acid • Dose: • Avoid use with renal impairment (CrCl <50) Probenecid. Lexi-Drugs Online, Lexi-Comp Inc. Hudson, OH. http://www.crlonline.com/crlonline. Accessed July 1, 2014. Medication Dose Probenecid 250mg po BID, titrated up to 500-2000mg/day Sulfinpyrazone 50mg po BID, titrated to 100-400mg /day
    71. 71. • Adverse Effects: – Cardiovascular: Flushing – CNS: Dizziness, fever, headache – Dermatologic: Alopecia, dermatitis, pruritis, rash – Gastrointestinal: Anorexia, dyspepsia, GERD, nausea – Hematologic: Anemia, aplastic anemia, hemolytic anemia (in G6PD deficiency), leukopenia – Skeletal: Precipitation of acute gouty arthritis, – Other: rash, hypersensitivity, uric acid nephrolithiasis
    72. 72. • Contraindication: History of urolithiasis, overproducers of uric acid, hypersensitivity to probenecid, small or large dose aspirin therapy, blood dyscrasias, <2 years of age, initiation during an acute gout attack • Precautions: – Disease-related: G6PD, peptic ulcer disease, renal impairment – Drug-related: Methotrexate, penicillin, salicylates
    73. 73. • Drug Interactions: – Salicylates – Penicillins/cephalosporins/carbapenems – Methotrexate – Pegloticase • Monitoring: serum uric acid, urine uric acid, renal function • Pt Education: Increase fluid intake ± urinary alkalization
    74. 74. • Place in Therapy: – “ALTERNATIVE” FIRST LINE therapy to xanthine oxidase inhibitors (XOI) – May be used in conjunction with XOI in patients not fully controlled on XOI alone • Cost: Probenecid 500mg (100 tablets) $114.56
    75. 75. • If patient has HTN or hyperlipidemia consider the use of losartan and fenofibrate • Both have uricosuric properties • Place in Therapy: add-on to XOI in pts not controlled on single agent Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    76. 76. • Mechanism of Action: Xanthine Oxidase inhibitor which causes reduced uric acid production • Dosing: Start at 50-100mg po daily – Titrate up every 2-5 weeks until a goal SUA <5-6 mg/dL – Doses >300mg usually given in divided doses – Max Dose=800mg/dAllopurinol. Lexi-Drugs Online, Lexi-Comp Inc. Hudson, OH. http://www.crlonline.com/crlonline. Accessed July 1, 2014. Dalbeth N, Kumar S, Stamp L et al. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients with Gout. J Rheumatol. 2006;33(8)1646-50.
    77. 77. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients with Gout. Methods Retrospective chart review of 250 patients attending rheumatology clinics in South Auckland between 2001 and 2004 diagnosed with gout Analysis Groups (n=250) •No allopurinol (n=23, 9.2%) •Lower than recommended allopurinol dose (n=22, 9.7%) •Recommended allopurinol dose (n=161, 70.9%) •Higher than recommended allopurinol dose (n=44, 19.4%) Inclusion Criteria American College of Rheumatology diagnostic criteria for gout Exclusion Criteria End stage renal failure receiving renal replacement therapy Dalbeth N, Kumar S, Stamp L et al. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients with Gout. J Rheumatol. 2006;33(8)1646-50.
    78. 78. Group SUA Number of patients achieving SUA ≤6mg/dL (0.36mmol/L) No allopurinol 0.57 mmol/L 1/23 (4%) Lower than recommended allopurinol dose 0.53 mmol/L 3/20 (15%, p=0.7 vs recommended allopurinol dose) Recommended allopurinol dose 0.48 mmol/L 29/152 (19.1%) Higher than recommended allopurinol dose 0.48 mmol/L 16/42 (38%, p<0.01 vs recommended allopurinol dose) Dalbeth N, Kumar S, Stamp L et al. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients with Gout. J Rheumatol. 2006;33(8)1646-50.
    79. 79. Dalbeth N, Kumar S, Stamp L et al. Dose Adjustment of Allopurinol According to Creatinine Clearance Does Not Provide Adequate Control of Hyperuricemia in Patients with Gout. J Rheumatol. 2006;33(8)1646-50.
    80. 80. • Renal: – Initiation of Therapy: • 50mg for people with CKD stage ≥ 4 • 100mg for everyone else – Chronic Therapy: • “Dose can be raised above 300mg daily even with renal impairment as long as it is accompanied by adequate education and monitoring for drug toxicity (e.g., puritis, rash, elevated hepatic transaminases; evidence B). • The ACR guidelines do not recommend the non-evidence based renal dose adjustment algorithm for maintenance dosing • Hepatic: no dose adjustments given Arthritis Care Res. 2012:64(10);1431-1446.
    81. 81. • Adverse Effects: – Dermatologic: Rash (<1%), Allopurinol hypersensitivity syndrome (AHS) – Hematologic: agranulocytosis, aplastic anemia, myeulosupression, thrombocytopenia – Renal: renal failure (<1%) • Contraindications: allopurinol sensitivity, concurrent didanosine • Drug Interaction: azathioprine, 6-mercaptourine (MUST reduce the dose of azathioprine or 6-MP when used in combination with allopurinol), theophylline, pegloticase, loop/thiazide diuretics, didanosine
    82. 82. • Monitoring: SUA every few weeks initially, HLA- B*5801 prior to initiation in high risk subpopulations (Koreans with stage 3 CKD or worse, and patients of Han Chinese or Thai descent). • Place in Therapy: FIRST LINE agent for chronic gout • Cost: 100mg (100 tablets) $24.24, 300mg (100 tablets) $60.81
    83. 83. • MOA: non-purine inhibitor of xanthine oxidase (XO) • Dosage: – Initiate at 40mg po daily; if goal SUA is not achieved by 2 weeks, increase to 80mg po daily – No renal/hepatic dosage adjustment in mild- Uloric [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2012.
    84. 84. • Adverse Effects: – Hepatic: abnormal LFTs – GI: nausea – Rheumatologic: Gout flares due to mobilization – Others: arthralgia, rash • Contraindications: Concomitant use of azathioprine/6-mercaptopurine
    85. 85. • Precaution: – Acute gout flare – Cardiovascular events – Hepatotoxicity • Drug-Interactions: azathioprine/6- mercaptourine, theophylline, pegloticase
    86. 86. • Monitoring: SUA after 2 weeks of treatment; LFTs at baseline and repeated if signs of hepatic injury • Place in Therapy: FIRST LINE alternative to allopurinol • Cost: – 40 mg (30 tablets): $256.99 – 80 mg (30 tablets): $256.99
    87. 87. Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout. Methods Randomized, multi-center, double-blind, phase 3 trial over a 52 week period Treatment Arms (n=760) •Febuxostat 80mg po daily (n=256) •Febuxostat 120mg po daily (n=251) •Allopurinol 300mg po daily (n=253) Primary Outcome Serum urate concentration of <6mg/dL at the last three monthly measurements Secondary Outcomes Proportion of subjects with SUA <6mg/dL at each visit, percentage reduction of SUA from baseline at each visit, reduction in the incidence of gout flares, reduction in tophus area, reduction in the number of tophi Becker MA, Schumacher HR, Wortmann RL et al. N Engl J Med. 2005;353:2450-61.
    88. 88. Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout. Results • Percentage of patients with SUA <6% at last 3 monthly visits • Febuxostat 80mg (53%)* • Febuxostat 120mg (62%)* • Allopurinol 300mg (21%) • Incidence of gout flares (day 1-week 8) • Febuxostat 80mg (22%) • Febuxostat 120mg (36%)* • Allopurinol 300mg (21%) Authors’ Conclusion Significantly more subjects receiving febuxostat v allopurinol achieved the serum urate concentrations <6mg/dL * p<0.001 compared to allopurinol
    89. 89. • MOA: pegylated recombinant modified mammalian urate oxidase (uricase) • Dose: 8mg IV infusion over 2 hours Q2 weeks; with corticosteroid and antihistamine pre- medicationKrystexxa [package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc; 2012 Sundy JS, Becker MA, Baraf HS, et al. Reduction of Plasma Urate Levels Following Treatment With Multiple Doses of Pegloticase (polyethylene Glycol-Conjugated Uricase) in Patients With Treatment-Failure Gout. Arthritis Rheum. 2008;58(9):2882-2891
    90. 90. • Adverse Effects: Gout flares, infusion reactions, nausea, vomiting, bruising, nasopharyngitis, constipation, chest pain, anaphylaxis • Contraindication: Glucose-6-phospate dehydrogenase deficiency Krystexxa [package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc; 2012
    91. 91. • Precautions: – Anaphylaxis: Most often occurs within 2 hours of the infusion; pre-medicate patients and observe them – Infusion reactions: Give the infusion over no less than 120 minutes; if a reaction occurs, the infusion should be slowed or stopped and restarted at a lower rate – Gout flares: Start gout flare prophylaxis with low dose NSAID or colchicine at least 1 week prior to starting pegloticase – Congestive heart failure: Some patients in clinical trials have demonstrated CHF exacerbations
    92. 92. • Drug Interactions: No studies of pegloticase with other drugs have been conducted • Monitor: SUA levels, G6PD screening prior to initiation in high risk patient populations (African and Mediterranean ancestry) • Place in Therapy: – Refractory disease – Must have all other forms of urate lowering therapy discontinued prior to its use • Cost: $10026 (8mg/mL, 1mL)
    93. 93. XO inhibitors: allopurinol, febuxostat XO inhibitors: allopurinol, febuxostat Uricosurics: probenecid, losartan, fenofibrate Recombinant uricase enzyme: Pegloticase X X
    94. 94. BSR EULAR ACR Goals of Therapy ≤ 5mg/dL ≤ 6mg/dL ≤6 mg/dL, and often ≤5 mg/dL Prophylaxis for Acute Gout Colchicine for up to 6 months; NSAIDs or COX-2 inhibitors in patients who cannot take colchicine for up to 6 weeks Prophylaxis in the first months of urate lowering therapy can be achieved with colchicine and/or NSAID First Line: NSAIDs or colchicine Second Line: Corticosteroids Uricosurics (i.e. probenecid) Second line drug in under-excretors or in patients resistant to allopurinol Alternative to allopurinol in patients with normal renal function “Alternative” first line tx w/appropriate renal function and intolerance or contraindication to XOI; add-on to xanthine oxidase inhibitors when not fully controlled Ann Rheum Dis. 2006;65:1312-24. Rheumatology. 2007:1-17. Arthritis Care & Research. 2012;64(10):1431-1446.
    95. 95. BSR EULAR ACR Allopurinol Drug of choice; Initial treatment starting at 50- 100mg/day and adjusted for renal function if necessary, to reach a therapeutic target of SUA <300μmol/L Appropriate therapy; start at a low dose (100mg/day), the dose must be adjusted for renal impairment First Line Febuxostat Not addressed Not addressed First Line Pegloticase Not addressed Not addressed Refractory disease Fenofibrate/ losartan Uricosuric Uricosuric Add on to appropriate XOI therapy Initiation of Therapy NOT during acute attack NOT during acute attack May start during acute attack if on prophylaxis Ann Rheum Dis. 2006;65:1312-24. Rheumatology. 2007:1-17. Arthritis Care & Research. 2012;64(10):1431-1446.
    96. 96. • Historically, we do not initiate urate lowering therapy during the acute attack due to risk of worsening the attack • New guideline recommendation from ACR states “pharmacologic ULT could be started during an acute gout attack, provided that effective antiinflammatory management has been instituted (level C)” • In practice, we are still waiting 1-2 weeks after Arthritis Care & Research. 2012;64(10):1431-1446.
    97. 97. Figure 3 from Arthritis Care & Research. 2012;64(10):1437. Long TermLong Term Monitoring:Monitoring: •SUA Q2-5SUA Q2-5 weeks duringweeks during ULT initiationULT initiation •SUA Q6SUA Q6 months whenmonths when stablestable
    98. 98. Table 4 from Arthritis Care & Research. 2012;64(10):1441.
    99. 99. • Unclear etiology of hyperuricemia • Refractory signs/symptoms of gout • Difficult to control and reach target SUA • Multiple/serious medication related adverse events Ann Rheum Dis. 2006;65:1312-24. Rheumatology. 2007:1-17. Arthritis Care & Research. 2012;64(10):1431-1446.
    100. 100. • Patient should be started on prophylaxis (low dose colchicine, NSAID, prednisone) just prior to or with the start of ULT • XOI (allopurinol/febuxostat) are first line • Uricosurics are usually second line or add on therapy, and should be avoided in over-producers • Pegloticase is used in refractory disease. All other ULT must be stopped prior to starting pegloticase. • Once on ULT, they should be maintained on ULT indefinitely. Should an acute exacerbation occur, the ULT should remain on.
    101. 101. These are being performed at the sameThese are being performed at the same time. We look to see if they need ULT,time. We look to see if they need ULT, start the prophylactic therapy, and thenstart the prophylactic therapy, and then start the ULT.start the ULT.
    102. 102. Date of download: 5/20/2014 Copyright © 2012 McGraw-Hill Medical. All rights reserved. Algorithm for management of hyperuricemia in gout. Legend: From: Chapter 74. Gout and Hyperuricemia Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014 From: Chapter 74. Gout and Hyperuricemia Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
    103. 103. Upon discussion with RT in the ER, the physician discovers this is the third exacerbation RT has had this year. He has only been given is 1.8mg total of colchicine thus far. What is the next thing that should be given to RT? A.Nothing—he is still in an acute exacerbation B.Probenecid 250mg po BID C.Colchicine 0.6mg po BID D.Naproxen 250mg po BID
    104. 104. What Urate Lowering Therapy would you want to start in RT, and why? A. Allopurinol B. Febuxostat C. Probenecid D. Nothing
    105. 105. When would you want to start urate lowering therapy in RT? A.Immediately, he is already on prophylactic therapy B.After he demonstrates appropriate response to his current treatment, which can double as prophylactic therapy C.1-2 weeks after his current flare subsides while he is on concurrent prophylactic therapy
    106. 106. • Should always be considered alone or in combination with pharmacologic therapy • Smoking cessation • Patient Education • Exercise • Weight loss • Avoidance of risk factors (dietary, medication) ~10-18%~10-18% decrease indecrease in SUASUA
    107. 107. Rheumatology. 2007;46:1372-1374. Ann Rheum Dis. 2006;65:1312-24. Arthritis Care Res. 2012:64(10);1431-1446.
    108. 108. Avoid Limit Encourage • Organ Meats high in purine (eg, sweetbreads, liver, kidney) • Serving Sizes of: • Beef, lamb, pork • Seafood with high purine content (eg, sardines, shellfish) • Low-fat or non-fat dairy products • High fructose corn syrup- sweetened sodas, other beverages, or foods • Servings of naturally sweet fruit juices • Table sugar, and sweetened beverages and desserts • Table salt, including in sauces and gravies • Vegetables • Alcohol overuse (defined as more than 2 servings/day for males and 1 serving/day for females) in ALL gout patients • Any alcohol use in gout during periods of frequent gout attacks, or advanced gout with poor control • Alcohol (particularly beer, but also wine and spirits) in all gout patients Figure 4 from Arthritis Care & Research. 2012;64(10):1439.
    109. 109. Given the following patient case, identify the options for non-pharmacologic treatment of gout: • RT is 6’4” and 240lbs • He exercises some mornings during the week • RT generally has coffee for breakfast, a pepsi with a roast beef sandwich for lunch, and scallops or steak with vegetables and beer for dinner.
    110. 110. • RT is 6’4” and 240lbs • Current Medications: metoprolol XL 50mg po daily, aspirin 81mg po daily, lisinopril 20mg po daily, metformin 1000mg po BID, furosemide 40mg po daily What medication risk factors does RT current have, and can we change any of his medications?
    111. 111. • Royal Pains: Season 2 Episode 10 (available on Netflix) – 13:20-14:33 – 28:37-29:45 – 33:25-35
    112. 112. • What would be in your differential diagnosis for this patient? • What signs/symptoms of gout does this patient present with? • Is this a typical acute gouty presentation?
    113. 113. A.Treatment plan is appropriate B. Treatment plan is inappropriate
    114. 114. A. Start the allopurinol as planned. B. Treat the acute attack, then start allopurinol C. Treat the acute attack, then start low dose colchicine and allopurinol concurrently D. Treat the acute attack and modify risk factors
    115. 115. • Acute – Non-Pharmacologic: rest, ice – Pharmacologic: • NSAIDs, colchicine, corticosteroids to treat (~7-10 day) • CONTINUE ULT during the acute gouty attack! • Evaluate if indicated for ULT: Tophi, CKD Stage ≥2, Urolithiasis, ≥2 acute gout attacks/year
    116. 116. • Chronic – Non-Pharmacologic: diet, fluids, weight loss, smoking cessation, avoidance of risk factors – Pharmacologic: • Prophylactic therapy: LOW DOSE colchicine, NSAIDs, corticosteroids during initiation or just prior to initiation of ULT • Urate lowering therapy (ULT) for indefinite duration dosed to SUA – Allopurinol/febuxostat> probenecid – Probenecid/losartan/fenofibrate may be add on therapy – Pegloticase last line for refractory cases Neoni T. Gout. N Engl J Med. 2011;364:443-52.
    117. 117. • We probably wont have time to work on these during class, but Elizabeth Akselrod, PharmD Class of 2015, and I made some practice cases and questions for you to work on at home while studying for the quiz/exam. • I will post our keys to the questions at the end of my version of the ppt slides after our lecture.
    118. 118. 1. Which of the following is the goal of urate lowering therapy? A. SUA <6mg/dL B. SUA <4 mg/dL C. SUA <7mg/dL D. Lower the SUA until the tophi resolve 2. Which medication(s) work on xanthine oxidase A. Allopurinol B. Febuxostat C. Pegloticase D. Probenecid E. Both A and B
    119. 119. 3) There is new evidence to support dosing allopurinol to a target serum uric acid, instead of renal dose adjustment a) True b) False 3) Low dose colchicine is less effective than high dose colchicine a) True b) False
    120. 120. 5) Patients being treated for gout should receive pharmacologic treatment only a) True b) False 6) When initiating urate lowering therapy, which of the following can be given to prevent acute gout attacks a) NSAIDs b) Colchicine c) Corticosteroids d) All of the above
    121. 121. • MC is a 21 yoF who presents to her PCP for an annual checkup. Her parents have been concerned because lately she hasn’t been taking good care of herself. She’s been staying up late, eating lots of processed foods, drinking excessive alcohol since her 21st birthday, and has developed a “strange obsession with sticking her tongue out at people.” She presents with no symptoms and simply wants to “get this appointment over with so she can go party in the USA.” • PMH: N/A • SH: Drinks 3-4 mixed drinks per day, quit smoking 4 weeks ago (1 pack per day) • Vitals: 98.6 F, BP 115/76, HR 80, RR 18, O2 Sat 98 • Medications: Women’s MVI, daily laxative use to help with weight loss • Abnormal labs: SUA 7.2 mg/dL • List all MC’s risk factors • Does MC need treatment for gout? If yes, what would you recommend? If no, explain.
    122. 122. • RW (prefers to be called Fat Amy) is a 28 yoF who was shooting a film in Hollywood when all of a sudden she felt pain in her right big toe which was red and inflamed. She presented to the ER 3 hours later and stated that her pain was a 4/10. She has no history of acute gouty attacks. • PMH: Type II DM, Obesity, GERD (no ulcers) • SH: 2 beers per night • SUA: 6.5 mg/dL; no tophi present • CrCl: 60 mL/min • What treatment options can you recommend for RW? • Does RW need chronic gout treatment? Prophylaxis? Explain. • Provide one counseling point using patient-specific language.
    123. 123. • TS is a 59 yoM who presents to the ER for the 4th time this year with an acute gouty attack. He rates his pain as a 6/10 and says it started 24 hours ago. His history is significant for HTN (refuses to take his Lisinopril because it makes him cough), DMT2, s/p MI in 2009, migraines, gouty attacks with tophi, and s/p vehicle accident with fractured femur. SUA: 8. G6PD (-) and HLA-B*5801 (-). • Recommend a plan for TS. Include drug name, dose, route and duration. • If the patient was HLA-B*5801 (+), which medication would you have to avoid? • Which medication(s) is contraindicated in G6PD deficiency?
    124. 124. • SN is a 63 yoM who has no significant PMH except has been taking Allopurinol 300 mg PO daily for 1 year due to frequent gouty attacks starting in 2005. At his annual physical, the doctor notes that SN has chronic knee pain and an SUA of 8.5 mg/dL. The doctor asks for your advice. Since you’re a gout expert, you know exactly what options are available and you recommend: • List 3 non-pharmacologic options to educate SN about:
    125. 125. • HR is a 45 yoF who has had breakthrough gouty attacks despite Allopurinol treatment. Her PMH is significant for HTN, DMT2, hyperlipidemia, s/p kidney donation in 2010, and recent start on Azathioprine for RA. She tells the doctor that she has heard of an alternative to Allopurinol that also doesn’t require renal dosing. What is this drug? Is HR eligible to receive this medication? Why/why not?
    126. 126. • Dr. Sampson is a new resident and wants to start a patient on Allopurinol for chronic gout treatment. He asks you for help to make sure the patient is eligible to take this medication. What test should be ordered prior to starting the patient on Allopurinol? • Which medications should you beware in the patient’s profile that interacts with Allopurinol?
    127. 127. • TY comes into your pharmacy to pick up his newly prescribed probenecid. He has never heard of this medication and knows nothing about it. You check his profile and confirm that he doesn’t have renal impairment and you approve the order. What important points should you make TY aware of?
    128. 128. • RC 67 year old African American male comes is a regular patient at your pharmacy. His past medical history includes Hypertension, diabetes, and atrial fibrillation. His current medication list includes: chlorthalidone 25mg po daily, metformin 1000mg po BID, aspirin 81mg po daily, verapamil 80mg po TID, and warfarin 5mg po daily. • VS: within normal limits; BG: 150 (fasting this AM) • He comes to your pharmacy with the following prescription. What would you want to do?
    129. 129. Colcrys 1.2mg po once followed by 0.6mg 1 hour later, then 12 hours later start 0.6mg po BID x 7 days. RC 67 7/6/14
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