LeeChuy, KatherineLee, Sidney Abert

Lerma, Daniel JosephLegaspi, Roberto Jose

Li, Henry WinstonLi, Kingbherly

Lichauco, RafaelLim, Imee Loren

Lim, Jason MorvenLim, John Harold

Lim, MaryLim, Phoebe RuthLim, Syndel Raina

Lipana, Kirk AndrewLiu, Johanna

Llamas, Camilla Alay

• Name: T. R.• Age: 60• Sex: M• Status: Married• Nationality: Filipino• Date of Birth: 12/10/1949• Place of Birth: Leyte• Religion: Roman Catholic• Educational attainment: High School Graduate• Occupation: retired; Grass cutter of Military Shrines Service• Current Address: Bataan• Informant: Patient, Wife, Niece, Nephew• Reliability: 70%

“Namamaga ang mga kasukasuan sa kamay, tuhod, at bukong-bukong hanggang

paa(swelling of the hands, knees and ankle to feet)”

• 10 years history of recurrent monoarthritis-No proper consult was done; self-medicated with paracetamol 500mg

+ ibuprofen 200mg (Alaxan) & paracetamol (Biogesic) 500mg-denied steroid intake and aspirin -pain free interval: 3 weeks initially, progressive shorter pain free

intervals-frequency of drug intake 3 tabs/day: taken as needed, initially TID-efficacy: slight relief of pain

4 months PTA • patient slipped and sustained an injury to the both hands and wrist in an attempt to break his fall

• admitted at a local hospital in Bataan• confined and was given unrecalled medications• relieved from the pain

-patient accidentally stepped on a sharp object and cleaned the wound site with guava leaves and betadine and then applied 500mg penicillin powder

-recurrence of joint pain and swelling of both hands, knees, and feet; self-medicated with Mefenamic acid 500 mg and amoxicillin 500 mg which provided relief, taken as needed

2 weeks PTA

1 week PTA -progression of joint pain and swelling of both wrist and hands, knees, ankles and feet, graded 10/10with limitation of movement these joints

ADMISSION (August 24, 2010)

• No major hospitalization, unrecalled immunizations• No allergy, no previous transfusion• (-) DM, PTB, Asthma, Cancer

Family History• not clear to the patient

Personal and Social History•Non-smoker

•Alcoholic beverage drinker ( 2 bottles beer; 3x a week and occasional gin drinker 2-3 bottles/week)

•Diet: mixed diet

•Denies illicit drug use

• General: no fever, no weight loss, (-) anorexia, (-) weakness, (-) insomnia• HEENT: no blurring of vision, no eye redness, pain, itchiness, no excessive

lacrimation, no ear pain nor tinnitus, no ear discharge, no epistaxis, no nose discharge, no anosmia, no obstruction nor sinusitis, no mouth sores, fissures, bleeding, no dental carries, no throat irritation,

• Pulmonary: no hemoptysis, no coughing, no dyspnea, no chest wall abnormality

• Gastrointestinal: no abdominal pain, no melena nor hematochezia, no changes in bowel habits

• Genitourinary: no hematuria, no dysuria, no urinary frequency, no hesitancy, no incomplete voiding

• Endocrine: no heat or cold intolerance, no polyphagia, no polydipsia, no polyuria, no thyroid enlargement

• Musculoskeletal: see HPI• Hematologic: no abnormal bleeding,easy bruising

PHYSICAL EXAMINATION

Admission (August 24, 2010)

General survey:Conscious, Coherent, stretcher-borne not

in respiratory distress

Vital signs:BP: 120/70PR:88 regularRR:22 cpmTemp: 36.5 C

Anthropometric mesaurement -Ht: 165.1 cm Wt: 65 kgs BMI: 23.9

August

General survey:• conscious, coherent, ambulatory, not in

cardiorespiratory distress, normal speech, appropriate thought process and content and well-oriented as to time, place and date.

• Vital Signs– BP: (RUE) 170/100

(LUE) 170/100– PR: 74 beats/minute– RR: 17 cycles/minute– Temperature (axillary): 37.2oC

• Anthropometric measurement -Ht: 165.1 cm Wt: 65 kgs BMI: 23.9

PHYSICAL EXAMINATION

Admission (August 24, 2010)Skin

Warm, dry skin, (+) scaling on the right foot and ulcers on the sole of the left foot

August 27, 2010

• Skin: Warm, moist skin, no jaundice, no skin discoloration, (+) tophi on the right wrist, right dorsum of the hand, right elbow, both feet, (+) ruptured tophi on dorsum on the right foot and sole of the left foot. (+)desquamation and non-healing wound on the medial calcaneal area of the left footNo rashes, petechiae, No palmar erythema, no spider angiomaNails without clubbing or cyanosis.

PHYSICAL EXAMINATION

Admission (August 24, 2010)HEENTPale palpebral conjunctiva, slightly icteric

sclera, 3-4 mm ERTLNo tragal tenderness, No nasoaural

discharge, nasal septum midline, no hoarseness

Supple neck, no palpable cervical lymph nodes, trachea is midline thyroid not enlarged

August 27, 2010

HEENTPale palpebral conjunctivae, anicteric sclera, pupils ERTL 2-3mm, no exophthalmos, no tragal tenderness, no aural discharge, supple neck, no distended neck veins, no palpable cervical lymph nodes, thyroid gland not enlarged

PHYSICAL EXAMINATION

Admission (August 24, 2010)RespiratorySymmetrical chest expansionNo retractions Equal vocal and tactile fremiti Resonant on percussion(+) crackles on both lower lung fields

August 27,2010Respiratory• Symmetrical chest expansion, no

subcostal retractions, unimpaired tactile and vocal fremiti , resonant upon percussion,(-) crackles on both lower lung bases, no wheezes, no rhonchi

PHYSICAL EXAMINATION

Admission (August 24, 2010)

CardiovascularAdynamic precordiumApex beat at 5th LICS MCSNo heaves and thrillsS1 > S2 at the apex, S2> S1 at the baseNo murmurs

August 27,2010

Cardiovascular• Adynamic precordium, AB at 5th LICS

MCL, no heaves, no lifts, no thrills, S1>S2 apex,S2>S1 base; Pulses were full and equal in all extremities, no cyanosis and clubbing

PHYSICAL EXAMINATION

Admission (August 24, 2010)Gastrointestinal

Flabby abdomen, Abdominal circumference: 98 cm, (+) shifting dullness, (+) venous collaterals, normoactive bowel sounds, no palpable mass, no tenderness,

tympanitic all over, liver span 10 cm MCL, Traubes space not obliterated, (-) Murphy’s sign , DRE: smooth rectal vault, no perianal tenderness, tight sphincteric tone, no masses, prostate not enlarge and greenish brown on examining finger

Genitourinary(-) CVA tenderness

DRE: greenish brown on examining finger

August 27, 2010GastrointestinalInspection: Globular and symmetrical

abdomen, No caput medusae, inverted umbilicus, no visible peristalsis, pulsation or mass

Auscultation: Normoactive bowel sound , No bruits

Percussion: tympanitic, Liver span 10 cm along the Right MCL, Traube’s space not obliterated, (-) shifting dullness

Palpation: Liver edge not palpable. No mass, (-) succusion splash, (-) fluid wave

Genitourinary(-) CVA tenderness, kidneys not palpable

PHYSICAL EXAMINATION

Admission (August 24, 2010)Musculoskeletal

Pulses full and equal, no cyanosis, (+) bipedal edema, (+) swelling on wrist to hands and ankle to foot, warm to touch, (+) draining abscess measuring 1 X 1 cm on the sole of the left foot

August 27, 2010Musculoskeletal(+) swelling on both wrists and hands,

ankles and feet, warm to touchCervical spine, L&R shoulder, left elbow,

and L&R knee joints with full ROMR elbow, L& R wrists, L&R MCPs, L&R

PIPs, L&R DIPs has limited ROMNo tenderness upon palpation.

PHYSICAL EXAMINATION

Admission (August 24,2010)Neurologic ExamGCS 15 (E4V5M6)Alert, oriented in three spheresIntact cranial nervesCerebellar – can do FTNT and APST with

easeMMT- 5/5 on all extremitiesNo sensory deficitsRefelexes: ++ on all extremities, (-)

Babinsky, nuchal rigidity, Brudzinki’s and Kernig’s

August 27, 2010

Neurologic Exam• Mental status: Conscious,

awake, alert GCS 15• Pupils 2-3mm, isocoric ERTL,

EOMs full and equal, no ptosis, no nystagmus

• No facial asymmetry, can shrug shoulders, can turn head against resistance

• MMT: cannot be assessed• No sensory deficits• Reflexes:

• Superficial: (+) Gag and corneal reflex

• Deep Tendon: not done

Physical Examination

Physical Examination

Physical Examination

Physical Examination

Physical Examination

Physical Examination

SUBJECTIVE DATA OBJECTIVE DATA

Age: 60

Sex: M

Swelling of joints of hands, feet and legs

Recurrent monoarthritis

Limitation of movements on the hands and feet

Alcoholic beverage drinker

BP 170/100(+) tophi on the right wrist, right dorsum of the hand, right elbow, both feet, (+) ruptured tophi on dorsum on the right foot and sole of the left foot. (+) desquamation and non-healing wound on the medial calcaneal area of the left foot(+) swelling on the wrists and hands, ankles and feet, which are warm to touch(+) pale palpebral conjunctivaDRE: greenish brown on examining finger

SALIENT FEATURES

Upon admission

• Given Clindamycin 300mg q 6h• Cold compress on affected areas, colchicine

(0.5 mg bid)• Send wound discharge for Gram’s stain and

culture

COMPLETE BLOOD COUNT

*8/23 8/25, after transfusion of 5 ‘U’ PRBC

Hemoglobin 48 68

RBC 2.43 2.89

HCT 0.16 0.21

MCV 63.30 73.20

MCH 19.7 23.60

MCHC 30 32.3

RDW 23.00 29.30

MPV 5.30 6.00

PLATELET 802 619

WBC 19.8 10.40

DIFFERENTIAL COUNT

NEUTROPHILS 0.89 0.90

METAMYELOCYTES 0.01 -

BANDS 0.01 0.01

SEGMENTED 0.89 0.89

LYMPHOCYTES 0.06 0.09

MONOCYTES - -

EOSINOPHILS 0.03 0.01

BASOPHILS - -

Reticulocyte count 33

UNIT REFERENCE RANGE

G/L 120-170

X 10^12/L 4.0-6.0

0.37-0.54

U^3 87 + - 5

Pg 29 + - 2

g/dl 34 + - 2

11.6 – 14.6

fL 7.4 – 10.4

x 10^9 / L 150 – 450

x 10^9 / L 4.5 – 10.0

0.50 – 0.70

0.00 – 0.05

0.50 – 0.70

0.20 – 0.40

0.00 – 0.07

0.00 – 0.05

0.00 – 0.01

x 10^-3 / L 5 - 15

8/23 8/25 8/26 8/28 9/01 Reference

Creatinine 2.86 2.29 2.21 2.08 1.82 0.5-1.2 mg/dl

BUN 65.70 8-23 mg/dL

Sodium 123 136.00 132.48 129.00 137-147 mmol/L

Potassium 4.96 4.47 4.21 3.36 3.8-5 mmol/L

iPO4 4.5 2.3-4.7 mg/dL

Ionized Calcium

1.66 1.52 1.42 1.37 1.32 1.12-1.32 mmol/L

Fasting Blood Sugar

78.97 78.97 70-110 mg/dL

SGPT - ALT 36.91 3.8-5 U/L

Uric Acid 13 4-8.5 mg/dl

HbA1c 7.90 4.8-6.0 %

8/26 8/28 Reference

Total Cholesterol 119.78 150-250 mg/dL

Triglycerides 130.33 10-90 mg/dL

HDL 22.03

LDL 68.20

Total Protein 7.00 6-7.8 g/dL

Albumin 2.57 3.2-4.5 g/dL

Globulin 4.43 2.3-3.5 g/dL

VG Ratio 0.58 1-3

Intact PTH 8.2 15-65 pg/ml

ESR 38 0-13 MM After 1 Hr

COMPLETE BLOOD COUNT

8/28 9/01 UNIT REFERENCE RANGE

Hemoglobin 117 105 G/L 120-170

RBC 4.56 4.16 X 10^12/L 4.0-6.0

HCT 0.36 0.33 0.37-0.54

MCV 79.80 79.80 U^3 87 + - 5

MCH 25.60 25.30 Pg 29 + - 2

MCHC 32.00 31.70 g/dl 34 + - 2

RDW 25.50 25.70 11.6 – 14.6

MPV 6.60 7.40 fL 7.4 – 10.4

PLATELET 450 268 x 10^9 / L 150 – 450

WBC 8.50 6.9 x 10^9 / L 4.5 – 10.0

DIFFERENTIAL COUNT

NEUTROPHILS 0.80 0.38 0.50 – 0.70

METAMYELOCYTES - -

BANDS - - 0.00 – 0.05

SEGMENTED 0.80 0.38 0.50 – 0.70

LYMPHOCYTES 0.13 0.52 0.20 – 0.40

MONOCYTES - - 0.00 – 0.07

EOSINOPHILS 0.07 0.10 0.00 – 0.05

BASOPHILS - - 0.00 – 0.01

Reticulocyte count x 10^-3 / L 5 - 15

Other Ancillary procedures:• Fecal occult blood test – (+)

• ECG – Sinus rhythm with left ventricular hypertrophy

• Urinalysis: albumin- negative, sugar – negative, RBC-0-2/hpf, Pus cell-1-4/hpf

X-ray of the left foot

September 1, 2010

X-ray of the right foot

September 1, 2010

X-ray of the left foot

September 1, 2010

Official X-ray findingsBoth feet• Multiple erosive and lytic changes involving the tarsal,

metatarsal, and phalangeal bones in both sides, with evidence of narrowing of the joint spaces.

• Calcaneal spurs are noted.• One notes evidence of soft tissue swelling, with soft tissue

lucencies, which may be due to abscess formation. .• Sclerotic changes are also noted involving the tarsocalcaneal

articulating surfaces on the right side.• One notes of decreased bone density.• Impression: • Above findings consider the possibility of Osteomyelitis.• The possibility of Gouty arthritis is not entirely ruled out.

Chest X-ray

Official X-ray findings

• Lung fields are clear.• There is increase in the transverse diameter of

the heart.• Aorta is calcified.• Diaphragm & sinuses are intact.• Impression:

CardiomegalyAtheromatous aorta

Anemia due to:Patient NSAID

GastropathyChronic Kidney

Disease

Hypochromic microcytic anemia

Hypochromic and microcytic anemia

(↓ iron)

Normocytic and normochromic

anemia (↓EPO)

(+) FECAL OCCULT BLOOD TEST + -

Chronic NSAID use(Alaxan-paracetamol+ibuprofen; Mefenamic acid)

+ -

Hct 16% <20-25% 20 to 30%

Hawkey CJ. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scand J Gastroenterol Suppl. 1996;220:124-7.

CATHERINE S. SNIVELY, M.D.,et.al. Chronic Kidney Disease: Prevention and Treatment of Common Complications. Am Fam Physician. 2004 Nov 15;70(10):1921-1928.

ADA Criteria for the diagnosis of diabetesTable 3—Criteria for the diagnosis of diabetes1. A1C ≥ 6.5%. The test should be performed in a laboratory using a method that is

NGSP certified and standardized to the DCCT assay.*OR

2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*OR

3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l).

*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.

American Diabetes AssociationDiagnosis and Classification of Diabetes Mellitus, DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010

Patient 8/23 8/25 8/26 8/28 9/01 Reference

Fasting Blood Sugar

78.97 78.97 70-110 mg/dL

HbA1c 7.90 4.8-6.0 %

In the setting of an elevated Hba1C but “nondiabetic” FPG, the likelihood of greater postprandial glucose levels or increased glycation rates for a given degree of hyperglycemia may be present.

American Diabetes AssociationDiagnosis and Classification of Diabetes Mellitus, DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010

Pending procedures

• Wound CS

-to determine etiology of the lesion as well as the sensitivity or susceptibility of the pathogen to antibiotics

Polarized light microscopy of specimen collected

September 2, 2010

Final Diagnosis

• Ruptured tophi on the right foot with secondary bacterial infection with osteomyelitis

• Acute gouty arthritis on top of chronic tophaceous gout

• Anemia secondary to occult GI bleeding probably due to NSAID gastropathy

• Chronic kidney disease secondary to gouty nephropathy and hypertensive nephrosclerosis

Management

Date Medications/ Treatments Frequency

8/24/10 Clindamycin 300 mg/ cap Q6h

8/24/10 – 9/1/10 Cold compress on affected area TID

8/25/10 Mupirocin ointment on affected area TID

8/26/10 –8/29/10

Ciprofloxacin 250 mg/tab BID

8/29/10 -9/3/10 Amlodipine 10 mg/tab OD

8/29/10 Omeprazole 40 mg/ tab OD

8/29/10 Paracetamol 500 mg/tab T >38.5 Q4h

8/29/10 Bisoprolol 2.5 mg/ tab OD

8/29/10 Aminoleban 1 sachet in 1 glass water BID

8/29/10 Sultamicillin 350 mg/ tab OD

9/1/10 Colchicine 0.5 mg/ tab OD

9/1/10 Apply ice compress 10-15 min over affected joints Q1h

9/3/10 Amlodipine 10 mg tab in am BID

9/3/10 Amlodipine 5 mg tab in pm

Clindamycin• reversibly binds to the 50S ribosomal subunits preventing

peptide bond formation thus inhibiting protein synthesis• 600 mg-1.8g/d q6-8h PO• Indicated for streptococci, S. aureus, and Bacteroides spp. • GIT: diarrhea, pseudomembranous colitis, nausea, vomiting;

HEPATIC: elevation of liver enzymes; CVS: hypotension; HEMATOLOGIC: eosinophilia; neutropenia, granulocytopenia, thrombocytopenia; LOCAL: sterile abscess at injection site; RENAL: renal dysfunction; MUSCULOSKELETAL: polyarthritis; OTHERS: hypersensitivity reactions

• Diarrhea and any inflammatory bowel disease, hypersensitivity to clindamycin or any component

Mupirocin ointment• inhibits bacterial protein synthesis by reversibly and

specifically binding to bacterial isoleucyl transfer RNA synthetase

• Apply 3x/d for 10 d• Skin infection• DERMATOLOGIC: polyethylene glycol {PEG} vehicle

may irritate broken skin or mucous membranes. Less frequent incidence: skin burning, stinging, pain, itching, rash and dry skin

• Hypersensitivity to mupirocin or any component, e.g., PEG

Amlodipine• acts primarily on peripheral vascular beds and have little

effect on cardiac muscle contraction or AV conduction• block the voltage dependent calcium channel inhibiting the

availability of intracellular calcium to interact with the myosin complex of smooth muscles. This action leads to relaxation of the smooth muscle allowing a decrease in peripheral resistance which leads to BP lowering

• 5-10 mg daily• Hypertension, angina• CNS: headaches; CVS: postural dizziness, palpitation,

tachycardia, ankle edema; DERMATOLOGIC: rash; OTHERS: flushing and fatigue

• hypotensive and hypersensitive to the drug and in instances of MI with heart failure or poor LV function.

Omeprazole• Irreversibly inhibits gastric parietal cell proton pump (H+-K+

ATPase, inhibit gastric acid secretion, both basal and stimulated

• 20-40 mg/d as single dose after breakfast for 4-8 wk PO• Reflux esophagiti, acid-peptic ulcer disease, Zollinger-Ellison

syndrome• CNS: reversible confusional states, agitation, depression,

hallucination; GIT: nausea, diarrhea, abdominal colic; Hematologic: agranulocytosis, pancytopenia, thrombocytopenia; Dermatologic : erythematous skin rashes, erythema multiforme, exfoliative dermatitis; Renal: interstitial nephritis, hematuria, glycosuria; Others: hypoglycemia, alopecia, blurred vision, arthralgia.

• Hypersensitivity to the drug, gastric malignancy

Paracetamol• It is a para-aminophenol derivative with analgesic and

antipyretic properties 325-650 mg (6-12 mg/kg) q4h, PO; max dose 4g/d

• Symptomatic treatment of mild to moderate pain and/or fever

• CNS: stupor, coma, euphoria; CVS: hypotension; DERMATOLOGIC: pruritus, urticaria; GIT: hepatic dysfunction, jaundice; GIT disturbances, nausea, vomiting; HEMATOLOGIC: leukopenia, thrombocytopenia, pancytopenia, methemogobinemia; RESPIRATORY: dyspnea, asthma; GUT: dysuria, interstitial nephritis and renal papillary necrosis

• Prolonged administration is contraindicated in patients with anemia or cardiac, pulmonary, hepatic or renal disease. Hypersensitivity to paracetamol or any of its component

Bisoprolol• Bisoprolol produces negative chronotropic effect

and minimal change in stroke volume • 5-10 mg PO once daily up to a max of 20 mg daily• Hypertension, angina, heart failure• CVS: bradycardia, AV block, sinus arrest, peripheral

vasoconstriction, heart failure; RESPIRATORY: bronchospasm; OPHTHALMOLOGIC: decreased tearproduction; OTHERS: fatigue

• Asthma and obstructive airway disease, Heart failure, second or third degree heart block, cardiogenic shock

Aminoleban

• 150 g/day (3 sachets/day)• Dietary supplement esp for patient w/ liver

impairment. Nutritional support to patients w/ chronic liver disease esp those w/ hepatic encephalopathy

• Diarrhea & nausea• Hypersensitivity

Sultamicillin• inhibits β-lactamases in penicillin-resistant

microorganisms and it acts against sensitive organisms during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide

• 375-750 mg bid• Respiratory tract infections, otitis media, UTI• Diarrhea, nausea, vomiting, rashes, pruritus, blood

dyscrasias, superinfections, dizziness, dyspnoea. Potentially Fatal: Anaphylaxis

• Hypersensitivity

Colchicine• mild anti-inflammatory drug with no analgesic effects. • inhibiting microtubule polymerization by binding microtubule protein

subunits and preventing their aggregation, thus disrupting membrane-dependent functions as chemotaxis and phagocytosis, which are cardinal events in the inflammatory response to precipitated crystals. It has no effect on the serum uric acid levels orits renal excretion

• 500 mcg tab taken orally hourly until pain and inflammation subside, to a maximum cumulative dose of 6.0 mg

• Acute attacks of gout and other crystal induced arthritis• GIT: nausea, vomiting, diarrhea and abdominal pain in up to 80% of

patients undergoing rapid colchinization; hepatotoxicity, hemorrhagic colitis with overdose or with liver or renal disease; HEMATOLOGIC: aplastic anemia, bone marrow suppression; CNS: peripheral neuritis; colchicine induced-myopathy and polyneuropathy with prolonged use; DERMATOLOGIC: alopecia, rash; OTHERS: anorexia, azoospermia, renal dysfunction with overdose or with liver or renal disease.

• Hypersensitivity to colchicine or any components Serious renal, gastrointestinal, hepatic or cardiac disorders Blood dyscrasia

Febuxostat: the evidence for its usein the treatment of

hyperuricemia and gout

Angelo L GaffoKenneth G Saag

Core Evidence 2009:4;25–36

Objective

• Review the clinical evidence of effectiveness of febuxostat (TEI-3420, or TMX-67) on outcomes and its potential for clinical management of hyperuricemia and gout.

Methods• Phases II and III

evidence• Literature searches

– PubMed– Cochrane database– American College of

Rheumatology– European League

Against Rheumatism• (?) Inclusion exclusion

criteria not mentioned

Febuxostat

• Orally administered, nonpurine selective inhibitor of xanthine oxidase.

• Binds to a channel in the molybdenum center of the enzyme, leading to a very stable and long-lived enzyme-inhibitor interactions with both oxidized and reduced forms of the enzyme

Phase II data

• 28-day, multicenter, double-blind, placebo-controlled, dose response clinical trial

• Determine safety and efficacy of once daily febuxostat– 40, 80, 120 mg

• Inclusion: patients with American College of Rheumatology criteria-defined gout aged 23-80y/o

• Exclusion: absence of kidney dysfunction or taking drugs known to affect serum urate (aspirin or diuretics)

Phase II data

• Cases of reduction seen in as early as 7 days after start of treatment

• Dose-dependent effect• Incidence of gout flares, due to sudden removal and

mobilization of uric acid crystals from the tissues– Despite pretreatment with colchicine

• Diarrhea, abdominal pain• Abnormal liver function tests

– 40mg (14%), 80mg (8%), 120mg (8%)

Other Phase II data

• Reductions on tophi volume (by MRI)• Good tolerance in allopurinol-intolerant patient• 3 month colchicine prophylaxis in patients starting

with febuxostat• Diarrhea, GI motility disorders, headache, abnormal

liver function tests, hyperlipidemia• Japan (128 patients)

– reduced SUA regardless of underexcretors or overproducers

– Safe and well tolerated– Abnormal liver function tests and gout flares

Phase III data

• FACT• APEX• EXCEL• CONFIRMS

Phase III data - FACT• Febuxostat versus Allopurinol Controlled Trial (FACT)• Randomized, double-blind, 52-week, multicenter

– Febuxostat 80 and 120 mg/day dose– Allopurinol 300 mg/day fixed dose

• Inclusion: adult patients with American College of Rheumatology-defined gout and SUA at least 8.0 mg/dL

• Exclusion: kidney dysfunction, concomitant drugs known to affect serum urate, BMI >50, active liver disease, pregnancy, use of prednisone >10 mg/d, or alcohol abuse

Phase III data - FACT

• Primary endpoint – SUA of 6.0 mg/dL• Clinical endpoint – reduction in tophus area,

change in number of tophi, and proportion of patients requiring treatment for acute gout flares

• Prophylaxis with colchicine or naproxen during a 2-week washout period

Phase III data - FACT

762 patients

254Febuxostat 80 mg/d

254Febuxostat 120 mg/d

254Allopurinol 80 mg/d

Discontinued 88 (34%)

Discontinued 98 (39%)

Discontinued 66 (26%)

Losses to follow-up, adverse events, and gout flares

Phase III data - FACT

Primary endpoint

Febuxostat 80 mg/d Febuxostat 120 mg/d Allopurinol 300 mg/d

53% 62% 21%

Phase III data - FACT

• Rates of total advers events and serious adverse events were similar

• Liver function test abnormalitis (4-5%), diarrhea (3%), headaches (1-3%)

• 4 patients in febuxostat group died– Cardiovascular events– Considered unrelated to administration of study

medications

Phase III data - APEX• Allopurinol and Placebo-Controlled, Efficacy Study of

Febuxostat (APEX)• Additional patients with mild to moderate renal

dysfunction (creatinine 2.0 mg/dL)– Febuxostat at 80, 120, 240 mg/d– Allopurinol 300 mg/d (crea 1.5mg/dL), 100 mg/d (crea 1.5-

2.0 mg/dL)• Inclusion: 18-85 y/o, American College of

Rheumatology-defined gout, SUA ≥8.0 mg/dL, creatinine up to 2.0 mg/dL

• Exclusion: intolerances to allopurinol, colchicine, naproxen, history of renal calculi, heavy alcohol intake, baseline transaminases ≥1.5 upper limit of normal

Phase III data - APEX

• More gout flares in febuxostat 120 and 240 mg/d arm in first 8 weeks

• Similar rates in 8-28 weeks• Diarrhea, liver function test abnormalities

1072 patients

Febuxostat 80 mg/d

Febuxostat 120 mg/d

Febuxostat 240 mg/d

PlaceboAllopurinol

300 mg/d or 100 mg/d

Phase III - EXCEL

• Open-label phase III extension of FACT• Continue evaluation response to treatment• Allopurinol compared to febuxostat failed to

achieve continuous reduction of SUA 6.0 mg/dL

735 patients

294Febuxostat

80 mg/d

294Febuxostat 120 mg/d

147Allopurinol

80 mg/d

Phase III - CONFIRMS

• Randomized, controlled, multicenter, double-blind

2269 patients

Febuxostat 40 mg/d

Febuxostat 80 mg/d

Allopurinol 200 or 300 mg/d

SUA <6mg/dL45%

SUA <6mg/dL 67%

SUA <6mg/dL 42%

Summary of evidence

Thank You!