Gout medications zagazig 2019

1. Medications for Gout
Safwat EL-ARABY
Rheumatology
EGYPT
D.D. Sepsis
Tolerability

2. Rheumatic Disorders
DCTD
SpAs
Degenerative
Metabolic
Infectious
Traumatic
Neoplastic
Paraneoplastic
Congenital / Hereditary
Pediatric & Juvenile
Bone Disorders
Endocrinal
Crystal-induced
Endogenous
Exogenous
MSU
CPPD
Basic CaPO4
GC ester
Methyl methacrylate
Talcum
Polyethylene
Apatite

3. Gout
Prevalence & Incidence
Pathophysiology
Epigenetics & Environment
Refractory Gout
Classic & Unusual pattern
Classification & Causes
Hyperuricemia Chronic Tophaceous Gout
Hyperuricemia vs Gout
Management of acute attack
Acute Gouty attack
Intercritical Gout
Associated conditions
Urate lowering Therapy
DCTD
Pathology
Renal disease
Etiology
Tophi
Genetics
Work up

4. Medications for Gout
D.D. Sepsis
Tolerability
Acute Gouty attack
Chronic Tophaceous Gout
Silent Deposition
Renal Disease
Basic Therapy
UL T : ULAs
Arthritis / Bursitis / Tendenitis / Enthesitis
Tophi

5. How to manage
Acute Gouty Attack ?
The most effective
Not public & impractical :
D.D. Sepsis
Tolerability
Why ?

6. Acute Gouty Arthritis
Successfully Terminated by
Colchicine
NSAID
GCs
ACTH
IL-1β Inhibitor
Treatment and Prophylaxis
Very expensive
Not approved in USA
Available in Europe
Canakinumab

7. Analogy : Urate Crystals are compared with Matches.
When the match strikes,” it causes a gout attack.
Colchicine : To eliminate future attacks / prophylactic
( the matches damp and harder to strike )
Uricosuric agents : actually (removes the matches) from the body.”
NSAIDs & Colchicine : To “put out the fire,”
They resolve the attack : but
“the matches are still there.”

8. Sooner
Colchicine :
is preferred for whom the diagnosis of Gout is not confirmed
Timing of the initiation of therapy
General considerations
Therapeutic Testing
NSAIDs :
are preferred when the diagnosis is secure
Generally,

9. Colchicine
Traditionally,
The oral dosing schedule : 0.5 or 0.6 mg / hourly until one of
3 Outcomes occurred :
Maximum of 10 doses
If No benefit:
You should ask yourself about the accuracy of the
diagnosis.
Doses every
2 to 6 hours
may Reduce –
adverse effects
Joint symptoms eased Nausea, Vomiting, or
Diarrhea developed
Maintain
Least effective dose
Prevention
Col COLMEDITEN 0.5 MG 100 TAB :50EGP

10. Colchicine
In 2009 (FDA) approved the First Single-ingredient Oral Colchicine
product for the treatment of :
Acute Gout Flares
Prophylaxis of Gout Flares
FMF in adults & children 4 years or older
COLCHICINE 500 MCGM 100 TAB
Sief Pharmacy : 50EGP
marketed as Colcrys

11. Colchicine
1.2 mg,
followed by 0.6 mg in 1 hour,
Low-Dose Regimen
New Recommendation for Colchicine
Tried in Acute Gouty Flares of < 12 hours duration
Old Protocol : up to 5 mg
for a total of 1.8 mg per attack

12. Starting with 1.2 mg, : Followed by 0.6 mg 1 hour later, and
then 0.6 every 12 hours until the attack has subsided
Colchicine
Early Gout Flare Control
Much Fewer adverse effects
For Prophylaxis :
0.6 mg once or twice daily as needed.
It should be started within 12 hours of attack onset
EULAR panel of experts : They recommend the low Dose Protocol
Low-Dose Approach vs High-Dose approach
Adjustment for : Renal Insufficiency :
Severe Renal Insufficiency should be started at
0.3 mg a day.
The 2012 ACR Guidelines : Confirm by Recommending
For those not responding

13. Usual dose is 1.2 to 2.4 mg daily.
Once or Divided
If adverse effects : Adjust the dosage
Colchicine
For Familial Mediterranean Fever
It is for treatment & prophylaxis of acute attacks of
Gout & FMF

14. It prohibited by the FDA in 2008 because of an unacceptable safety profile, with the potential for serious adverse events, including death, with IV
administration.
Peak plasma concentrations occur within 2 hours of oral administration.
Its plasma half-life is 4 hours
It has a low therapeutic index, with Steady-State Plasma concentrations
from 0.5 to 3 ng/mL and Toxic effects occurring at app. 3 ng/mL
Therefore, in most patients, the adverse effects Precede or Coincide with the improvement in joint symptoms.
Colchicine
IV administration
Pharmacokinetic :
Steady-State Plasma concentrations

15. It must be stopped promptly at 1st sign of GIT adverse effects
Adverse
effects :
In 50% to 80% of patients using the : Old, High-dose Regimen
Include increased peristalsis, Cramping abdominal pain , Diarrhea, Nausea, and Vomiting.
The risk of Myopathy is increased with the concomitant use of colchicine and other drugs with potential myotoxicity, such as Statins and
HCQ
The drug may produce a reversible : Axonal NeuroMyopathy
It is most often seen in patients with :
Hypertension, Renal dysfunction, or Liver disease who are also taking Diuretics.
Rhabdomyolysis
It is more common in people who are also taking a Statin & Cyclosporine.
Long Term

16. NSAIDs
They are preferred :
In a patient with an : Established diagnosis
Uncomplicated gout
Indomethacin being the traditional choice.
It is effective in doses as low as 25 mg four times a day
Generally Recommended :
Initial dose of 50 to 75 mg, followed by 50 mg / 6 to 8 H : Maximum, 200 mg in 1st day
To Prevent Relapse :
Continue for an additional 24 H and then taper to 50 mg every 6 to 8 H for the next 2 days.
Oral Naproxen, Fenoprofen, Ibuprofen, Sulindac, Piroxicam, and Ketoprofen, as well as IM Ketorolac, are also
effective , Also COXibs

17. Gout Flares occurring in organ transplant patients who are taking Prednisone at maintenance doses of 7.5 to 15 mg a day
Corticosteroids
IA GCs
are useful in the treatment of acute gout limited to a single joint or bursa
Oral , IM or IV GCs :
Reserved for
High doses : 0.5 mg / kg OR at least 20 to 60 mg/day , are necessary.
Dose :
Intolerance OR
Contraindications to
NSAIDs & Colchicine : e.g.
Peptic ulcer / Renal disease
Evidence :
Lower doses may not be effective,
Of choice for Bursitis / Tendeitis / Enthesitis

18. Branded ACTH gel initially approved by the FDA for a variety of indications in 1952,
It was reapproved in 2010 to treat
AdrenoCorticoTropic Hormone ( ACTH )
Single injections of IM ACTH gel (25 to 80 IU) can terminate an acute gout attack
More often, however, repeated administration is required every 24 to 72 hours.
This treatment is effective post-operatively and may be more effective than GCs
Why ?
Possibly because of the mechanism of
action
In addition to stimulating the adrenal cortex to produce GCs, ACTH interferes with the acute inflammatory
response through Activation of Melanocortin Receptor
Infantile spasms, exacerbations of MS , and 17 other indications.
Ironically, Acute Gout was not one of those indications.

19. In early 2013, the European Commission approved Canakinumab for :
Frequent gout attacks (at least 3 attacks in the past 12 months) and
NSAIDs and colchicine are contraindicated, Not tolerated
No adequate response, OR
GC s are inappropriate.
IL-1 B Inhibition
IL-1β : plays a critical role in the initiation of Gout attacks,
Biologic inhibitors of IL-1β for both the treatment and prophylax of acute gout
Although approved for the treatment of TNF receptor–associated periodic fever syndromes, these expensive agents have not yet been approved in
the US for gout
Indications :
FDA : Concerns about cost and adverse effects in elderly individuals
Administered as a single, SC injection of 150
mg.

21. Acute Gouty Arthritis
Prophylaxis

22. Prophylaxis
App. 50% :
will experience acute flares after initiation of ULT
Colchicine
Small daily doses prevent acute attacks in up to 85%
Colchicine, 0.6 mg one to three times a day, is generally well tolerated

23. In patients who are unable to tolerate Even One Colchicine tablet per day,
Use : indomethacin or another NSAID
(e.g., indomethacin,25 mg twice a day, or naproxen, 250 mg a day or twice a day)
Some patients may require combination therapy of Colchicine and NSAIDs.
Peptic ulcer disease prophylaxis should be considered in at-risk patients.
Prophylaxis : For How Long ?
IF : Colchicine is intolerable

24. Prophylaxis is usually continued until
Serum Urate value : maintained well within the Normal Range
No acute attacks have occurred for 3 to 6 months.
Prophylaxis : For How Long ?
The 2012 ACR Guidelines for Management of Gout :
Continuing prophylaxis for 6 months,
OR
3 months After achieving Target serum urate : Without Tophi,
OR
6 months After achieving Target serum urate : with Resolution of Tophi
Target : 4 OR 5 OR 6 mg/dl
Recommend
3 choices :

26. Prophylactic Colchicine
may block the acute inflammatory response but does not alter the deposition of crystals in
tissues.
Is it right to give Prophylactic colchicine without controlling Hyperuricemia ?
When deposition continues without the warning signs of
recurrent bouts of acute arthritis, tophi and destruction
of cartilage and bone can occur without notice.
Donot Neglect Hyperuricemia
Therefore : Prophylactic treatment is not recommended unless the clinician also uses ULAs
Why ?

28. Hyperuricemia

29. Level of Saturation
Sugar Crystals
Salt Crystals
Cholesterol Crystals
Sugar Crystals

30. Physically : Serum Urate Level of Saturation
6.8 mg/dL.
Level of Saturation
Hyperuricemia :
is defined as a serum urate concentration 6.8 mg/dl
404 mcmol/L
0.40 mmol/L
Hyperuricemia +
Saturation +
Nucleation +
Crystallization +
Deposition =
Acute attack of gout &/or Crystal growth

31. Effect of Environment & Life Style

32. 30 %
10 %
Top Causes of Joint Pain
Gout = 1/10
Regional Pain Syndromes were excluded

33. USA
EU
Japan
How many patients have Hyperuricemia ?
How many developed Gout ?
How many diagnosed ?
How many receiving ULT ?
1/3
1/2
2/3
> 330 > 508 > 127
6.5% 4% 7.5%
Industrial ( Developed ) World

34. Prevalence :
Clear increase in incidence in recent years, Why ?
Rising incidence and prevalence of Gout and Hyperuricemia
attributed to the
Aging population
Health Epidemics :
.
Metabolic syndromes,
Obesity,
Type 2 Diabetes,
Hypertension ,
Thiazide Diuretics ,
CKD
Dietary issues with regards to Purine
and Fat intake

35. Associations / Triggers / Risk factors / Causes for secondary / Strategy for Therapy
Those patients more susceptible to develop Hyperuricemia & gout

36. > 60 % of gouty patients have Metabolic Syndrome
Each element of MS are 2-3 times more frequent amongst gouty patients

37. Dietary Nucleic acids ( DNA & RNA )
Degraded in the small intestine lumen
Cellular Nucleic acids ( DNA & RNA )
DNA/RNA in cells degraded (Turnover)
Purine Turnover
Sources of Uric Acid
Fasting
Pathophysiology
Total urinary UA excretion = 600 mg / day

38. High Fructose Corn Syrup
is a low-cost sweetener that replaced sugar in thousands of products over the past 30 years.
In 1970,
Americans consumed less than
a pound of the syrup per year.
In 2005,
the average was
42 pounds, according to The
Seattle Times.

39. Purine Turnover
Sources of Uric Acid
~10% of filtered
Uric acid is excreted
Overproduction is associated with Overexcretion / Donot use uricosurics
Excretion
Locations of Urate Deposition = Locations of high acidity / filtration / reabsorption /
Secretion OR Excretion

40. Types
According to Pathophysiology
According to Causative Factors
According to Triggers
According to Severity
According to the Course
According to associations
According to Co-morbidities
Collecting good data = Optimal Strategy

41. It is caused by decreased Renal UA excretion in > 90% of patients
and Overproduction of urate in < 10% of patients.
No Renal disease
No Congenital disease
No Myeloproliferative disease
According to known Causative Factors
Primary Hyperuricemia
Some but not all cases of primary gout have a Genetic Basis.
Unknown

42. It is related to Overproduction OR Decreased Clearance as a direct or indirect consequence of the primary disease process.
What are the primary disorders causing :
Urate Overproduction & Those causing
Urate Underexcretion
There is primary congenital or acquired disease
Secondary Hyperuricemia
Known Cause
According to known Causative Factors

43. Secondary Hyperuricemia
Cause Increased Urate production Decreased Urate Excretion

44. Hyperuricemiawith Acute
Gouty Attack
Refractory Hyperuricemia
Hyperuricemia :
Urate Nephropathy
Hyperuricemia
with chronic Tophaceous gout
Hyperuricemia
More frequent / Severe / Duration & Polyarticular
Classification of Hyperuricemia :
in relation to Course
Why ?
2ry Hyperuricemia / Diuretic + low dose aspirin

45. Why ?

47. Asymptomatic H
Asymptomatic with deposition
During acute Gouty attack
Intercritical
Silent Tophi
Chronic Tophaceous gout
Secondary
Primary
Types of Hyperuricemia
Urate Level
Age
Associations
Refractory
Urate Nephropathy
Is strategy of therapy , the same ?
Dialysis / with & without anuria
Transplanted
Kidney Functions / eGFR

48. Hyperuricemia ( 10.5 mg / dl ) /
66 years old /
Diuretic + Low dose Aspirin /
Intercritical /
eGFR ( 60 ) /
165/90 mmHg /
Dyslipidemic
( To be more specific Hypertriglycerdemia )
Write prescription for following patient
Write prescription for hyperuricemic patient with SUA ( 10.6 mg/dl )

49. Hyperuricemia : Outcome
Asymptomatic ( 2/3 )
But
,
may
1/3
1
3
2
4
5
10-20 years
10 years more

50. Gout
Chronic
Tophaceous Gout
Systemic
Features
Non classic
Unusual
presentation

51. Testing : For Hyperuricemia
Serum Uric Acid Level 6.8 mg / dl
404 mcmol / L
0.40 mmol / L
Kidney Function Tests :
Total UA excretion / 24 hours
Creatinine Clearance
Urinary UA to Creatinine Ratio
Microalbuminuria
Urates in Sediment
pH
Full Urine Analysis
Serum Creatinine
eGFR
Creatinine Clearance
BUN
Lipid Profile
Dyslipidemia
High Triglycerides
Low HDL-Cholesterol
CBC
Myeloproliferative disorders :
Polycythemia
Lymphoproliferative disorders
Hypothyroidism
Insulin Resistance
Blood Sugar Fasting
Random
Hba1c
T3 , T4 , TSH

52. Associated Conditions :
Obesity
Hypertriglyceridemia
Glucose intolerance
Hypertension
Atherosclerosis, and
Coronary Artery Disease
Hypothyroidism.
If you have Hyperuricemia OR Gout : Think about :
Work up for detection :

53. Urate lowering Therapy
Urate Lowering Drugs

54. Why ?

55. Target Serum Level
Duration of ULAs
Tools

56. Target Serum Urate Goals
Recent recommendations
< 5.0 mg/dL ( <300 μmol/L )
may be needed to control the disease in some patients, including those with Tophi
< 6.0 mg/dL (<360 μmol/L)
( Most of Guidelines )
ULT reduces the long-term risk of recurrent flare by app.
60% for each 1 mg/dL decrease in sUA
Evidence : < 6.0 mg/dL is important for the
Depletion of total body urate stores.

57. Duration of Urate-Lowering Therapy
Reductions from continuous ULT to an “intermittent” regimen in previously stable Gout lead to significantly higher flare rates
In asymptomatic patients with Gout successfully treated with prior ULT,
Withdrawal of Therapy
often results in an abrupt increase in sUA, with recurrent attacks occurring in 1/3 of patients within 2 years
Some reports suggest that ULT should be “Lifelong” in patients with gout.
Why ?
ULT discontinuation
in the setting of Tophaceous Gout leads to recurrent gout flares in a vast majority and recurrent tophi in nearly half

58. Systematic Non Pharmacologic & Pharmacologic
Therapeutic Approaches to Hyperuricemia
Urate Lowering Therapy
Patient Situation Patient Education
Diet / Lifestyle
Treatment Objectives
Management of Associations
Urate
Lowering
Agents
Strategy

59. (1) Xanthine Oxidase (XO) inhibitors
(Allopurinol and Febuxostat),
considered as first-line agents
(2) Uricosurics
( Probenecid,
Benzbromarone
Sulfinpyrazone )
(3) Uricases
(Pegloticase)
Available ULAs classes include :

60. XANTHINE OXIDASE
INHIBITION
Allopurinol
Ted R. Mikuls :Urate-Lowering Therapy , CHAPTER 66 , P:1061 , Kelley,s & Firestein Textbook of Rheumatology , 10 th Edition , 2017

61. Allopurinol
Allopurinol
Mechanism of action of XO Inhibitors

62. (1) Low Cost,
(2) Once-daily Oral administration,
(3) Effectiveness ( in under excrete & overproduce UA )
(4) Favorable Safety Profile, and
(5) Potential effectiveness with Renal impairment.
Available for approximately 50 years,
It accounts for a vast majority of all ULT prescriptions
Allopurinol
It has several advantages:
Significant Declines in sUA
Decreased Gout Flare Rates
Declines in Tophus area
Allopurinol treatment results in
Achieve Goals

63. Role in Rheumatic Disease and Indications
Approved indications for allopurinol include
(1) Treatment of Hyperuricemia in Gout,
(2) The management of Hyperuricemia resulting from the treatment of malignancy
(most often Leukemia or Lymphoma)
(3) The management of Nephrolithiasis ( due to increased urinary UA excretion
It is not approved for Asymptomatic Hyperuricemia
Hyperuricemia is independently associated with CV morbidity and mortality , giving rise to speculation that ULT could be
Cardioprotective.

64. XO inhibition via Allopurinol also has been shown to :
Role in Rheumatic Disease and Indications
Many prospective studies :
Allopurinol : showed Lower all-cause mortality risk among receivers
Pediatric Essential Hypertension,
Allopurinol use resulted in significant, albeit modest, declines in blood pressure
Improve endothelial function,
Improving measures of both local and systemic blood flow Improvements in Renal function in at-risk
populations

65. Pharmacology
Allopurinol Oxypurinol ( Active )
Metabolized
Peak serum conc.
1-2 hours
Plasma Half Life
1-2 hours
Peak serum conc.
4-5 hours
Plasma Half Life
~ 15 hours
Therefore : Once daily Dose
Elimination
Glomerular filtration
Elimination
Glomerular Filtration
Some Tubular Reabsorption
Therefore : Plasma Half Life
Increased with Renal Insufficiency
Allopurinol Hypersensitivity Syndrome
(AHS) developed more likely with Renal insufficiency

66. Dose and Drug Administration
Available for treatment and/or prevention of Tumor Lysis Syndrome
In USA : Approved at daily doses as high as 800 mg daily
Europe : Approved in up to 900 mg daily
In every day clinical practice
It is rarely administered at doses exceeding 300 mg/day
Pills – 100 mg Pills – 300 mg
Once-daily Oral
Split Dosing is acceptable for daily doses 600 mg or Higher
IV Allopurinol : Allopurinol Sodium 500 mg

67. Dose and Drug Administration
The most commonly used dose.
300 mg / day
Only app. 40 % achieve < 6 mg/dl
Only app. 1/4 achieve < 5 mg/dl
Increased to 75% with 600 mg daily

68. Patients who achieved the target required a median daily dose of 400 mg
Recent Gout Treatment Guidelines
Data from two studies suggest that each 100 mg increase in Allopurinol leads to an additional decline in sUA approaching
1.0 mg/dL
“ Start Low and Go Slow ” approach
92% success in achieving sUA treatment goals in Gout.
Start with 100 mg daily
Increased by 100 mg every 2-5 weeks as required to achieve the target

69. General Consensus :
Initial Allopurinol Dosing
should be adjusted for diminished renal function ,which prolongs the plasma half-life of Oxypurinol.
If GFR < 20 mL/min : initial daily dose of 100 mg or less with even lower doses for those with more severe renal
impairment.

70. Toxicity
It is uncommon ( 0.1% to 0.4% )(1 in 56,000 ) but potentially fatal
90% of cases occurring within 60 days of allopurinol initiation
It is characterized by the presence of an erythematous desquamating rash (similar to Stevens-Johnson syndrome), Fever,
Eosinophilia, and end-organ damage, including hepatitis and renal failure
The use of Low Starting Doses, adjusted for renal function, may by itself reduce AHS risk by approximately 10-
fold
Ask your patient to discontinue allopurinol if a Rash develops, particularly if accompanied by fever or
mucocutaneous lesions.
Allopurinol Hypersensitivity Syndrome
The most serious

71. Rebound flares
It is most prominent in the early phases of drug initiation and can be mitigated by anti-inflammatory prophylaxis.
less than 5 to 10% of those exposed are intolerant to the drug
The most common complication

72. It is classified as a Pregnancy Category C agent
(animal reproduction studies have shown an adverse effect on fetus without adequate human studies).
Fertility, Pregnancy, and Lactation
Both allopurinol and oxypurinol are expressed in
Breastmilk, and because drug effects in the developing
infant are largely unknown, it should be administered to a
nursing mother with caution.

73. Febuxostat
Ted R. Mikuls :Urate-Lowering Therapy , CHAPTER 66 , P:1061 , Kelley,s & Firestein Textbook of Rheumatology , 10 th Edition , 2017
It is a potent (XO) inhibitor : Chemically distinct from
allopurinol.
It is not Purine analoue
It an important alternative for whom allopurinol is not
effective ( intolerance or lack of efficacy )

74. It exert potential benefits beyond the treatment of Gout :
improvements in vascular function in patients with tophaceous gout.
Role in Rheumatic Diseases and Indications
Not For : Asymptomatic Hyperuricemia.
Alternative means of XO inhibition,
For allopurinol intolerance ( unique structure )
It prevents further reductions in renal function in patients with CKD

75. Pharmacology
Oral administration
50% absorption
Peak plasma concentrations within a few hours
Metabolism occurring primarily in the liver
Peak urate-lowering effects occur during the first 5 to 7 days of treatment.
Drug Elimination occurs via both hepatic and renal pathways.

76. Dose and Drug Administration
Febuxostat is available in
40 mg tablets in the United States, in
80 mg tablets doses in the United States and Europe, and
120 mg tablets doses in Europe
The usual dosing ranges from 40 mg to 120 mg daily
increase to higher doses (80 mg to 120 mg daily)
Initiating dose : (40 mg to 80 mg daily)
2 weeks If sUA levels remain > 6 mg/ dl

77. The primary end point was achieved by
53% , 65%, & 69% of patients receiving daily doses of
80 mg, 120 mg, and 240 mg, respectively,
compared with 21% to 22% of patients receiving fixed-dose Allopurinol.
Dose and Drug Administration
Secondary Outcome : Declines in both gout flare rates and an approximately 70%to 80% reduction in gout tophus area during follow-up. (
as with Allopurinol )
Febuxostat : Metabolized primarily in the liver : It may not require renal dosing

78. Toxicity
Common:
Gout flare;
Skin rash;
Nausea;
Arthralgias;
LFT abnormalities
Rare:
CV events (unclear association);
Cytopenias

79. It is not known whether the drug is excreted in human milk and febuxostat should be used only with caution in nursing
women, because its effects in developing infants are unknown.
Fertility, Pregnancy, and Lactation
The effects of febuxostat on fertility are not known
Febuxostat is labeled as Pregnancy Category C

80. URICOSURICS
Probenecid
Sulfinpyrazone
Benzbromarone
The most common Agents
( 24-hour urine UA, < 700 mg )

81. Uricosurics
They represent the first class of ULT to be used in gout treatment.
They diminish the post secretory reabsorption of UA
Why ?
~ 90 because of Underexcretion
Probenecid is the most widely used uricosuric in gout
treatment
Primarily because of concerns of treatment related toxicity, Sulfinpyrazone and Benzbromarone are less widely available, and neither is available
in the United States

82. “Secondary” Uricosurics
Anti-hypertensive ( 50 mg/day ) resulted in mean sUA declines of approaching 9%.
Salicylates
( <1 g/day) : inhibition of active secretion with lower doses
(>4 to 5 g/day) : inhibition of UA reabsorption at higher doses
Losartan

83. Is Routine Urinary UA excretion / 24 hours could correct the equation
Why :
Although potentially effective for a majority of patients with gout
They are much less commonly used than allopurinol
They designated as Second-line ULTs in Gout management guidelines
Is it / Because XO inhibitors are suitable to both types
Are XO inhibitors more safe : for Primary * Secondary outcomes ?
In UL : Uricosuric therapy accounted for < 5% of all ULT prescriptions
Uricosurics

84. Dose and Drug Administration
Probenecid : 500 to 2000 mg daily in divided doses
It (500 mg) is also formulated with colchicine (0.5 mg) as a combination tablet
In a Study : probenecid, 1500 mg/day was associated with a 32% reduction in plasma urate concentration
Other studies : softening of tophi, functional improvement , and improved pain symptoms.
These drugs may lose effectiveness in patients with moderate to
severe renal insufficiency
probenecid can be used effectively in select patients with mild to moderate CKD.

85. Benzbromarone maintained its hypouricemic effect even among patients with a Cr CL as low as 20 to 40
mL/min
Benzbromarone
It is administered once daily and may be effective in patients with moderate renal impairment.
Benzbromarone treatment in usual doses (50 to 200 mg/day)
leads to between 25% and 50% reductions in sUA in
addition to decreases in gout flare rates and tophi
Among patients intolerant to or experiencing treatment failure with allopurinol 300 mg/ day, 92% of those administered benzbromarone (200 mg /
day) achieved a sUA less than 5.0 mg/dL compared with 65% of those receiving probenecid (2000 mg/day)
Sulfinpyrazone
It is given in divided doses at an initial daily dose of 200 to400 mg, increasing to 800 mg daily, if
necessary to achieve target sUA goals.

86. Toxicity
Rebound gout flares
Uricosuric therapy is associated with an increased risk of
Nephrolithiasis
HOW TO AVOID ?
Optimizing fluid intake and
Alkalinizing the urine ( urine pH higher than 6.0 )

87. the combination has been shown to yield a more rapid resolution of tophi than Allopurinol monotherapy
Uricosurics may also serve as effective adjuvants to XO inhibition
Allopurinol monotherapy (200 to 300 mg/day)
Failed
Add
Probenecid (1000 mg/day)
86% achieved a target sUA of < 5 mg/dL
Combination Therapy :

89. The target serum urate is < 4.0 mg/dL ( Why ? )
To achieve a timely reduction in the total body urate burden
Through the use of
Xanthine Oxidase inhibitors,
Uricosuric agents, OR
Uricases.
If you have extensive Tophi :
How to achieve these levels pharmacologically ?
Pegloticase

90. They facilitate the conversion of UA into Allantoin; the latter is far
more soluble.
URICASES
Pegloticase

91. It is a modified mammalian uricase
It is a biologic parenterally administered agent and represents the most recently approved
ULT in gout.
Pegloticase
Antigenicity and an immune response directed towards the drug are major limitations in the repeated dosing
of pegloticase.
IV Pegloticase : Rapid and Marked declines in sUA, which may be particularly important in
the rapid depletion of total-body urate levels.
8mg

92. It is characterized by :
Severe disabling Gout,
Accompanied by marked Tophaceous deposition and
Significant Comorbidity,
in which conventional ULT is
either Contraindicated or Ineffective
Role in Rheumatic Disease and Indications
Pegloticase is approved for the treatment of hyperuricemia in patients with treatment Refractory Gout.
Treatment- refractory disease

93. In clinical trials :
Pegloticase use resulted in
plasma concentrations as low as
0.5 to 1 mg/dL within
24 hours of an initial dose
Role in Rheumatic Disease and Indications

94. Pegloticase / other uricases :
could play a role as an induction therapy in select patients with severe
tophaceous gout and excessive total body urate stores
Pegloticase administration has been associated with
Dramatic regression of Tophi118 and depletion of Urate Stores,
Role in Rheumatic Disease and
Indications
Therefore :

95. Photographic and radiographic evidence of
tophus resolution after pegloticase treatment in
patient 1.
A, Large draining tophus on fifth distal
interphalangeal (DIP) joint, before treatment. C,
Corresponding radiograph showing soft tissue
swelling and bony erosions in fifth DIP joint, before
treatment.
B, Resolution of tophus on fifth DIP joint after 12
weeks of treatment.
D, Corresponding radiograph showing resolution of
soft tissue swelling in fifth DIP joint, a decrease in
bony erosions, and thickening of bone cortex at this
joint,
15 months after termination of therapy.

97. Pegloticase is approved for intravenous infusion administered during a 2-hour period at a dose of 8 mg
every 2 weeks
Patients received prophylaxis
against infusion reactions and
against rebound gout flares
(colchicine, NSAID, or glucocorticoid).
Dose and Drug Administration

98. Toxicity
The most common serious adverse event observed with pegloticase therapy is Anaphylaxis, observed in approximately 7% of
patients
Antipegloticase antibody can be detected in a vast majority of patients (~90%)
Anaphylaxis occurred despite prophylaxis ( antihistamine and GCs ) with an onset of symptoms typically seen within 2 hours of
drug administration
The concomitant use of other ULT should be avoided
Rebound gout flare is common after the administration of pegloticase.

99. No studies have examined the impact of pegloticase on either fertility or pregnancy in humans, and it is unknown whether pegloticase is excreted in
human milk.
In the absence of appropriate human studies, pegloticase is classified
as Pregnancy Category C and it is not recommended for use in nursing mothers.
Fertility, Pregnancy, and Lactation

100. Efficacy loss
It is defined as sUA rising higher than 6.0 mg/dL during treatment, appears to be strongly associated with the
formation of Antipegloticase Antibodies
(1ry (Ig) M and IgG subtypes that bind the PEG portion of the drug).

101. URATE-LOWERING DRUGS
IN DEVELOPMENT

102. In a 3-week study of 60 patients with gout (all with baseline sUA >8.0 mg/dL), 31% to 36%of patients given ulodesine (40 mg, 80 mg, and 120 mg daily) achieved a final sUA of
< 6.0 mg/dL.123Decreases in sUA ranged from 2.7 to 3.4 mg/dL compared with a decline of just 0.4 mg/dL with placebo.
Ulodesine
inhibiting endogenous UA synthesis via the inhibition of purine nucleoside phosphorylase
Lesinurad
Food and Drug Administration(FDA) in December, 2015.
In contrast to probenecid,65 the co-administration of lesinurad does not appear to increase the renal elimination of oxypurinol or
febuxostat,125suggesting that this may be an ideal uricosuric to use in combination with first-line XO inhibitors.
Tranilast
Uricosurics: urate-lowering properties, possible therapeutic effects including allergy,
malignancy, and conditions characterized by excessive tissue fibrosis.
Arhalofenate dual uricosuric and anti-inflammatory effects
Levotofisopam

103. Hyperuricemia
Albuminuria
Chronic Kidney Disease > 13 mg
Hypertension
Urate Nephropathy
Uric Acid Nephropathy
Nephrolithiasis
Urolithiasis
Renal Disease

104. In Pre-Eclampsia : increase in the serum urate level
as a result of a decrease in the renal clearance of urate
Urates during Pregnancy & Labor
Maternal serum urate concentrations normally decrease during pregnancy until the 24th week
then increase until 12 weeks after delivery
Perinatal mortality : is markedly increased when maternal plasma urate levels are raised, usually in association with early-onset pre-
eclampsia.
The highest mortality rate is seen with serum urate concentrations higher than
6 mg/dl & diastolic blood pressure greater than 110 mm Hg
Labor itself is associated with an increased serum urate level, and it remains elevated for 1 to 2 days after delivery.

105. URATE-LOWERING DRUGS
In Renal Insufficiency

109. Strategy
In different Situations

110. These agents are equally effective in preventing the deterioration of renal function in patients with primary gout
In most cases, Allopurinol is the drug of choice because it can be used with fewer restrictions compared with Uricosuric agents.
Gouty patient
Hyperuricemic
UA excretion < 800mg / day
Normal Renal Functions
You can use :
Xanthine Oxidase Inhibitor OR
Uricosuric drug.
Situations :

111. When uricosuric agents are prescribed, patients should be counseled to
avoid salicylate use at doses greater than 81 mg/day
The ideal candidate for Uricosuric agents
Gouty patient
Younger than 60 years and has
Normal Renal function
(Creatinine Clearance >80 mL/ min),
UA excretion of < 800 mg / day on a general diet
No history of Renal Calculi.
Situations :

112. Gouty patient
UA excretion > 1000 mg / day in their urine OR
who have a history of Renal Calculi of any type
In which Xanthine Oxidase Inhibitor ( XOI ) : is the drug of choice
The incidence of renal calculi is about 35% in patients with primary gout who excrete > 700 mg/day of UA
The risk for uric acid stones is also greater upon initiation of Uricosuric therapy.
Patients with Tophi generally should take a XOI to decrease the load of urate that must be handled by the kidney.
Situations :

113. Failure of Uricosuric Agents to produce a serum urate concentration < 6 mg/dL
OR : Intolerance of the uricosuric agent.
Gout and mild Renal Insufficiency
be given either type of agent,
But Probenecid and Sulfinpyrazone :
would not be expected to work when the GFR < 50 mL/min.
Allopurinol is effective in the presence of renal insufficiency,
But doses may need to be decreased in that situation.
Febuxostat needs no adjustment in mild to moderate renal insufficiency.
Final indication for a XOI
Situations :

114. It is only appropriate for those patients with Tophaceous Gout
with a large excess of total body urate and Persisting Gout attacks,
OR with
Damaging Arthropathy
who are intolerant of or who have failed conventional treatment
When to prescribe Pegloticase ?

115. Receiving UL Agents ? Not receiving UL Agents
Should not be Stopped
Should not be Started
Should not be Increased
Because a sudden lowering of serum urate levels is known to precipitate acute attacks,
An inflammatory reaction that is already in progress may be substantially worsened by a major drop in the serum urate concentration
Why ?
What about Acute Gouty attack associated Hyperuricemia ?

116. COMPLIANCE & Reimbursement

117. Ancillary Factors

118. Tumor Lysis Syndrome