GOUT GOUT ARTHRITISARTHRITIS

Blondina Marpaung

Rheumatology DivisionInternal MedicineDepartment

Medical Faculty Sumatera Utara University

Hippocrates abad ke-5 :

Podagra

Galen abad ke-3 :

Tophi

Leeuwenhoek 1679 :

Tophi crystal

SYDENHAM 1683

­ self suffered Gout - clinical finding

SCHEELE 1776­:­Uric­acid­in­urine ­­­­­­­­-­renal­stone

WOLLASTON­Uric­acid­from­thopus

GARROD 1856­­Hyperuricaemia­test­in­Gout

EMIR FISCHER

­­Structure­of­­purine

-­Corelation­uric­acid­with­purine

Inflammation process due to crystal deposition in tissue joint /

deposisi kristal asam urat pada jaringan sendi/sekitar (tophi).

Gout (gutta/drop) exist as “ evil drop ”

in to joint

“ The King of Diseases and The Disease of King ”

GOUTGOUT ARTHRITIS = JICHT = PIRAI = GOUTARTHRITIS = JICHT = PIRAI = GOUT

METABOLISM DISORDERMETABOLISM DISORDER­

:­­­­­­­­­­­­­­­­­­­­-­Arthritis acute violent recurrent parroxysms

- Hyperuricemia

- Deposits Sodium Urate ( Thopi )

- Calculi Uric Acid ( Kidney )

HYPERURICEMIAHYPERURICEMIA­:­1.­Over­Production­of­Uric­Acid

­­­­­­­­­­­­­­­­­­­­­­2.­Reduced­Excretion

­­3.­Combination­1­&­2

NORMAL VALUENORMAL VALUE­:­­Man­ ­3,5­-­6,0­mg­/­100­cc

­­­­­­­­­­­­Women­­­3,0­-­5,0­mg­/­100­cc

­­­­­­­­­­­­Children­3,0­-­4,0­mg­/­100­cc

NEVER GOUT :NEVER GOUT : ­Hippokrates

­ ­ 1.­EUNUCH­Hippokrates

­ 2.­Before­MENOPAUSE

­ 3.­Before­COITUS

“­MAN­will­suffered­gout­if­know­­and­passionate­a­woman”

“Woman­will­suffered­gout­if­doesn’t­passionate­a­man”

GoutGout Clinical syndromesClinical syndromes due to due to monosodium-monosodium-

urat monohidrat (MSU)urat monohidrat (MSU) crystal crystal deposit deposit Deposit Deposit ccristal MSU ristal MSU at the joint will ariseat the joint will arise

acute acute inflaminflammmaation attacktion attack Onset Onset acuteacute : : attack onattack on acute acute artritis artritis

monoartikuler monoartikuler leg jointleg joint Complete remisionComplete remision, , remision with high remision with high

frequency that occurs more frequentlyfrequency that occurs more frequently

Painful arthritis episodic Painful arthritis episodic

intermitten, monoarticular, foot thumb, intermitten, monoarticular, foot thumb,

ankle and knee jointankle and knee joint

Can develop to oligo or poliartikulerCan develop to oligo or poliartikuler

Tends to NSAID and steroid abuseTends to NSAID and steroid abuse

Can be trigger by stress, ex operation, Can be trigger by stress, ex operation,

blood tranfusion.blood tranfusion.

Perjalanan Klasik Gout Perjalanan Klasik Gout

3 stage : hiperurikemia asimptomatik, gout akut intermiten dan gout kronik tofaseous

The stage from hiperurikemia asimptomatik to gout kronik tofaseous is variation from a patient to another.

Dependent from factor endogen and factor eksogen.

Artritis Gout AkutArtritis Gout Akut

Gout acute attack is so painful. Gout acute attack is so painful.

Mainly occurs at early morning and its peak in Mainly occurs at early morning and its peak in couple of hours. couple of hours.

The patient cant prop up their own weight, more The patient cant prop up their own weight, more over touch the blanket also can make the patient over touch the blanket also can make the patient in pain.in pain.

The skin color is red and hot, body sudfebril,The skin color is red and hot, body sudfebril, leukositosis, LED leukositosis, LED andand CRP CRP elevation.elevation.

Diffrential DiagnoseDiffrential Diagnose: infe: infectionction

Urid acid level in serum cant be use to diagnose a Urid acid level in serum cant be use to diagnose a Gout, the level can be high, normal or decrease.Gout, the level can be high, normal or decrease.

Analizing joint liquid with polarize microscope can Analizing joint liquid with polarize microscope can diffrentiate gout or infection/pseudogout.diffrentiate gout or infection/pseudogout.

1. monosodium urat crystal presipitation (consentration > 9 mg/dl)

- cartilage

- synovium

- para articular tissue (bursa)

- tendon and tendon sheath

* Uric acid sheated with protein stimulates

neutropil with IgG crystal formation.

Gout attack phase

2. Response leucocytePMN :

Crystal produces chemotaksis factor

PMN response

crystal phagoscytosis by leucocyte.

3. phagoscytosis :

Cristal difagositosis by leukosit

formates phago lisosom

vakuole membrane been surrounded by kristal join with membrane leukositik lisosom.

4. Kerusakan lisosom

Hidrogen binding with the cristal surface nenbrane lisosom.

damage the membran lisosom,

and release the enzim and radical oxide in the sitoplasma.

5. Cell damaging

enzim lisosom release in the sinovial fluid

imflamation response elevation intensity

tissue damaging

Uric acid :

•­The­main­End­Product­from­Met.­Purine.

•­excreted:­­-­­via­Kidney

­­­­­-­­via­intestinal­tract.

Normal­G.­F.­R.­­+­Hyperuricaemia

­uric­acid­excretion­­via­urine­:­Normal

except­:

­­­­uric­acid­concentration­­>­9­mg­/­100­ml­in­serum

High uric acid concentration

•­Not­always­­:­GOUT

­­­­­­­­Renal­stone

SERUM URIC ACID :SERUM URIC ACID :­

•­Higher­level

•­Longer­duration­(­persistent­)

­­Higher­possibility­have­gout

INCREASED FORMATION OF URIC ACID :INCREASED FORMATION OF URIC ACID :

1.­SPECIFIC­ENZYME­ABNORMALITIES

=­HYPOXANTINE­-­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­GUANIN­PHOSPHORIBOSYL­­­­­­­­­­­­­­­­­­­­­TRANSFERASE­ACTIVITY­

=­PHOSPHORIBOSYL­PYROPHOSPHATE

­­­­SYMTHETASE­ACTIVITY­

2.­TURN­OVER­OF­NUCLEOPROTEIN­

=­DIET­(­PURINES­)

DECREASED EXCREATION OF URIC ACIDDECREASED EXCREATION OF URIC ACID

­­­1.­ALTERATION­IN­RENAL­FUNCTION­AND­

­­­­­­CONTRACTION­OF­EXTRACELLULAR

­­­­­­FLUID­VOLUME

­­2.­DRUGS­(DIEURETICS)

­­3.­LACTIC­ACIDAEMIA

­­4.­STARVATION­AND­KETOSIS

­­5.­ESSENSIAL­HYPERTENTION

­­6.­LEAD­POISIONING

­­7.­HYPERCALCAEMIA

Urate crystals from synovial fluid viewed with compensated polarised light

Slide­8

•­All­­Over­The­World­And­Ras

•­Negro­Less

•­South­East­Asia­and­Pasific

•­Polynesia­&­Micronesia

•­Filipines­(­in­U.S.)

•­Maori­(­New­Zealand­)­10.­2/­100­(highst)

•­INDONESIA­??

›­Intake­purine,­alcohol

›­clearance­uric­acid

›­kidney­function­&­hypertension

FILIPINA

NEW­ZEALAND

POLINESIA

•­Lesser­Uric­acid­excretion­­

•­Low­intake­purine­from­diet

•­Changes­diet­pattern­­(­high­purine,­alcohol­)­­uric­acid­serum­level­increase­,­always­have­GOUT

CLINICAL FEATURES :CLINICAL FEATURES :

•­MTP-I­acute­and­explosive•­fever­&­malaise•­uric­acid­stone•­recurrent­after­1-2­years

•­tophi­:­MTP,­olecranon,­synovium,­bursa,­achilles ­­­forearm,­helix­of­the­ear

•­pres.factor­:­-­stress­­­­­­­­­­­­­-­trauma­­­­­­­­­­­­­-­dehydration­­­­­­­­­­­­­-­purine­&­alcohol­intake­­­­­­­­­­­­­-­drug

Slide 11Slide 11

Slide 6Slide 6

Slide 7Slide 7

Classic­podagra:­acute­gouty­arthritis­of­first­metatarsophalangeal­joint

Acute gouty olecranon bursa

Deforming gouty arthritis

Gout patient :Kidney stone is the first sign, before is gouty arthritis

AS.U.DARAH PADA BATU (%) 5 - 7 mg% 83 9 = 11% 7 - 9 mg% 472 87 = 18% 9 - 11 mg% 498 123 = 25%11 - 13 mg% 144 41 = 28% › 13 mg% 38 20 = 53%

AS.U.URINE PADA BATU (%) 300 - 500 360 72 = 20% 500 - 700 317 66 = 21% 700 - 900 154 53 = 34% 900 - 1100 39 15 = 40% › 1100 18 9 = 50%

Serum Uric Acid

‹ 8 mg % 90% without tophi 8 - 9 mg % 70% without tophi 9 - 10 mg % 50% without tophi10 - 11 mg % 46% without tophi › 11 mg % 29% without tophi

‹ 5 th 70% without tophi

10 th 50 % without tophi 15 th 39% without tophi 20 th 29% without tophi 40 th 26% without tophi

RONTGENT :RONTGENT :

•­PUNCHED-OUT­AREA­PADA­PERMUKAAN­SENDI­

•­BONE­EROTION­

•­JOINT­DESTRUCTION

•­SUBCUTANEUS­TOPHI

•­CALCIFICATION­OF­TOPHI

•­ASIMMETRICAL­PERIARTICULER­SWELLING

DIAGNOSISDIAGNOSIS APPROACH APPROACH Suspect Gout : Monoartritis at young male Artritis acute at MTP I, talocruralis or knee Artritis with hiperurisemia

Aspiration and joint fluid analyze

MSU + MSU –

See the 12 criteria ACRDo it match 6 from

12 criteria that its have

Check serum uric acidAnd

Urine uric acid 24 hours

Not GoutGout

Observation and evaluate others examination

Using light microscope

And polarization

DIAGNOSIS :DIAGNOSIS :

•­Anamnese­&­clin.­Features

•­Urate­crystal­in­the­joint­fluid

•­Urate­crystal­in­the­tophi

•­Cholchisine­Response­Dramatically­­(oral:­1­-­48­h­;­IV­:­1­-­12­h)

PRESENCEF 6 OF THE FOLLOWING 12 :

­­1.­­­More­than­one­attack­­2.­­­Max.­inflam.­Developed­within­1­day­­3.­­­Attack­of­monarticular­arthritis­­4.­­­Joint­redness­­5.­­­MTP-I­joint­paintfull­or­swollen­­6.­­­Unilateral­attack­involving­MTP-I­7.­­­Unilateral­attack­inv.­Tarsal­joint­8.­­­Suspected­tophus­9.­­­Hyperuricemia­10.­­Asimetric­swelling­within­a­joint­11.­­Subcortical­cyst­without­erosion­12.­­Neg.­microorganism­culture­of­joint­fluid

DIFFERENTIAL DIAGNOSIS :DIFFERENTIAL DIAGNOSIS :

•­Pseudogout•­Rheumatoid­Arthritis•­Rheumatoid­Variant•­Osteoarthritis•­Sarcoidarthritis•­Psoriatic­Arthritis•­Infectious­Arthritis•­Cellulitis•­Acute­Bursitis•­Acute­Rheumatic­Fever

Hiperurikemia Hiperurikemia

Its not the only conditin to diagnose Gout.Its not the only conditin to diagnose Gout.

The The RiRisksk fromfrom gout gout rise with the stage and therise with the stage and the longer oflonger of hiperurikemia hiperurikemia

Hiperurikemia Hiperurikemia can be cause by a lot of condition, can be cause by a lot of condition, genetigeneticc or acquiredor acquired, metaboli, metabolicc oror renal. renal.

Hiperurikemia asimptomatiHiperurikemia asimptomatic cant make the things c cant make the things worst before it turn to Gout.worst before it turn to Gout.

PENGOBATAN GOUTPENGOBATAN GOUT

Prevent acute attack: cold compress, NSAID, Prevent acute attack: cold compress, NSAID, kolkisin, (artrosentesis)kolkisin, (artrosentesis)

Change the life styleChange the life style Cure the disease that’s occurCure the disease that’s occur Avoid the risk factors, ex drugsAvoid the risk factors, ex drugs Defend the normourikemiaDefend the normourikemia Proflaksis to avoid the acute attackProflaksis to avoid the acute attack

•­Immediate­control­of­acute­attack

•­Prevent­Recurrent

•­Prevent­Complications

­­1.­­=­Colchisine­:­0,6­mg/h,­max.7­mg/d­(oral)­­­­­­­­­­­­­­­­­­­­­­­­­­­­

­­2­mg­in­Saline­20cc,­max.4­mg(i.v)­­­­­­­­­­­­­=­­­NSAID­­­2.­URICOSURIC­­­:­Probenecide,­Sulfinpyrazon

­­3.­URICOSTATIC­:­Allupurinol­(Zyloric)

Beware of Over diagnose and Beware of Over diagnose and over treatedover treated

Simptom­muskuloskletal­and­hyperuricemia­

but­Non-Gout­­no­needed­drug­lowering­uric­acid

Pengobatan artritis gout akutPengobatan artritis gout akut

ColchicineColchicine,, NSAIDs dan kortikosteroid, NSAIDs dan kortikosteroid, cold application, cold application,

arthrocentesisarthrocentesis can be use to prevent the acute attac can be use to prevent the acute attac

TerapTerapyy to make the serum uric acid decreace, therefore is to make the serum uric acid decreace, therefore is

best not to be donebest not to be done in acute phase, it will slow down the in acute phase, it will slow down the

healing process.healing process.

The drug choosing is depend on efication, attack condition The drug choosing is depend on efication, attack condition

and the patient condition.and the patient condition.

ColchicineColchicine

PreventPrevent fagositosis fagositosis uric cristaluric cristal byby neutrofil neutrofil

Block the realease of chemotactic factorsBlock the realease of chemotactic factors

Decrease the mobility and adhesi leucosyt Decrease the mobility and adhesi leucosyt polimorfonuklearpolimorfonuklear

Prevent phosphorilation of tyrosin and formingPrevent phosphorilation of tyrosin and forming leukotrin Bleukotrin B44

Inhibits upregulated neutrophil-endothelial adhesionInhibits upregulated neutrophil-endothelial adhesion

Increases cAMPIncreases cAMP

Inhibits crystal-induced tyroisne kinase activationInhibits crystal-induced tyroisne kinase activation

Selectively inhibits mediator release (e.g. decreases Selectively inhibits mediator release (e.g. decreases IL-1 and chemotactic cytokine release, but not IL-1 ra IL-1 and chemotactic cytokine release, but not IL-1 ra antagonist)antagonist)

Inhibits crystal-induced PLA2 activity, and PLAP and Inhibits crystal-induced PLA2 activity, and PLAP and LTB4 releaseLTB4 release

ColchicineColchicine Oral Oral

Efective dose is closer to the side effect inEfective dose is closer to the side effect in traktus gastrointestinaltraktus gastrointestinal

Primary dosePrimary dose 1 mg, 1 mg, continue withcontinue with 0.5 mg 0.5 mg afterafter 2 2 hourhour until it feel discomfort atuntil it feel discomfort at abdomen / diare abdomen / diare oror total total dose dose 8 mg. 8 mg.

The pain loss inThe pain loss in 18 18 hourshours & diare 24 & diare 24 hour.hour. 75- 80% pasien inflama75- 80% pasien inflamation decreasetion decrease inin 48 48

hourshours Caution to patient with liver and kidney problem Caution to patient with liver and kidney problem

and to old person.and to old person.

Acute Gout prophylaxis therapyAcute Gout prophylaxis therapy

Acute Gout attack can be prevent with small Acute Gout attack can be prevent with small dose of colchicine or OAINS.dose of colchicine or OAINS.

Profilaksis therapy must be given before Profilaksis therapy must be given before loweringlowering hiperurikemia hiperurikemia level been done.level been done.

Profilaksis Profilaksis withwith colchicinecolchicine,, proven to prevent proven to prevent the recurrent attack, whether in normal level of the recurrent attack, whether in normal level of uric acid or not. uric acid or not.

The period of the therapy is at least one year The period of the therapy is at least one year after serum uric acid concentration is back to after serum uric acid concentration is back to normal.normal.

May be added NSAID if May be added NSAID if colchicinecolchicine is proven is proven ineffective.ineffective.

WHEN TO TREAT WHEN TO TREAT HYPERURICEMIA?HYPERURICEMIA?

If the cause is uncorrected, for example If the cause is uncorrected, for example obesity, hypertension, hypercholesterolemia.obesity, hypertension, hypercholesterolemia.

Two or three true gout attack per year. Two or three true gout attack per year. Gout with tophy.Gout with tophy.Gall bladder stone > 800 mg/day.Gall bladder stone > 800 mg/day.Tumor lysis (acute uric acid nefropathy risk).Tumor lysis (acute uric acid nefropathy risk).

URICOSURIC AGENT

•­PROBENECID

•­SUPHIN­PIRAZONE

­­­­-­Renal­tubular­reabsorption­inhibition.­­­­­-­Increasing­urinary­output

•­SALICILATE­DOSIS­TINGGI­

URISCOSTATIC AGENT

•­ALLOPURINOL

­­­­-­COMPETITIVELY­INHIBIT­­­­­­XANTINE­OXIDASE­ENZYME.

­­­­-­PURINE­­BIOSYNTHESIS­SUPPRESSION

­­­SERUM­AND­URINE­URIC­ACID­DECREASING­CONCENTRATION

USUAL­DOSE­300-­400­mg­SINGLE­DOSE(­INITIAL­DOSE­100­mg­GRADUALLY­INCREASING­DOSE)

­Rapidly­decreasing­uric­acid­serum,­causing­gout­attack­by­the­beginning/first­week­may­appear,­indication­for­:­­­­­­­­­­­­­-­COLCHISINE­­3­x­05,­­­­­­­­­­­­­-­PHENYLBUTAZON­3­x­100,­­­­­­­­­­­­­-­INDOMETHACINE­­3­x­25,­­­­­­­­­­­­­-­NSAID

Uricosuric agentUricosuric agent

Increase uric secretion. Indicated for low uric Increase uric secretion. Indicated for low uric clearance patient.clearance patient.

Dangerous if high urine uric acid concentration.Dangerous if high urine uric acid concentration. Contraindicated for low urine streamContraindicated for low urine stream ( ( <<1 1

ml/ml/minuteminute), ), kidney stone history or inadequate kidney stone history or inadequate renal functionrenal function ( ( CCT <CCT < 50 ml 50 ml/m)/m)

PProbenesid 1 g robenesid 1 g -- 2 g 2 g /day, effect(-) if/day, effect(-) if CCT <CCT < 50 50 ml/mml/m

Sulfinpirazon 50 – 100 mg Sulfinpirazon 50 – 100 mg 2x/day2x/day, , gradually gradually increase by increase by 200 200 - - 400 mg 400 mg 2X/day. Ineffective if 2X/day. Ineffective if renal impairment exist.renal impairment exist.

XXanthine-oxidase anthine-oxidase inhibitorinhibitor(Alopurinol)(Alopurinol)

Preventing late stage of uric acid synthesis.Preventing late stage of uric acid synthesis. Indicated for high uric acid productionIndicated for high uric acid production Main side effectMain side effect alopurinol alopurinol : hypersensitivity: hypersensitivity Capable of lowering uric acid serum in Capable of lowering uric acid serum in

overproduction and under excretion or bothoverproduction and under excretion or both Given dose is adjusted by creatinine swap Given dose is adjusted by creatinine swap

value.value.

GOUT AND DIETGOUT AND DIET

Purine in diet : Purine in diet : NOT NECESSARILLY CAUSING NOT NECESSARILLY CAUSING concentration serum uric acid of more than 1.0 concentration serum uric acid of more than 1.0 mg/dl.mg/dl.

ADEQUATE Purine consumption (compared to ADEQUATE Purine consumption (compared to constant low purine diet) indicated to those constant low purine diet) indicated to those who usually consume high purine diet.who usually consume high purine diet.

Low purine diet consumption in HIGH Low purine diet consumption in HIGH QUANTITY produce INCREASING PURINE QUANTITY produce INCREASING PURINE LOAD than high purine consumption in small LOAD than high purine consumption in small quantity.quantity.

BAHAN MAKANAN YANG BOLEH DAN TIDAK BOLEH DIBERIKAN

­­­­­­­­­­­­INGREDIENTS­­­­­UNPROHIBITED­­­­­­­­­ PROHIBITED

­­­­FOOD­­­­­ ­­­­­ ­­­­­­­­­­­­­­­FOOD­­­­­­

­carbo ­ ­­­­all­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­-­hydrate

­animal­ ­­­­­meat/chicken,­ sardine.­clamshell,­heart­,­protein­ ­­­­­tuna,­ liver,­gut,­spleen,­lung

­­­­­tenggiri,­bawal,­ brain,­meat­extractdaging/kaldu­­­­­bandeng­50­g­/h duck,­bird

­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­egg,­milk

­­ ­­­­­beans,­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ -­protein­ ­­­­­emping­25g,

­­­­­tofu,­tempe­and­­­­oncom­50­g­sehari

­fat­­­­­­­­­­ ­­­­­limited­amount­of­ -­­­­­­­­­­­­­­­­­­­­­­­ ­­­­­oil­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

­­­­­­­­­­­­­­­­INGREDIENTS­­­­­­­­UNPROHIBITED­­­­­­­­­ PROHIBITED

­­­­­­FOOD­­­­­­­­­­­­­­­­­­­­­­­­ FOOD

vegetable­­­­­­­ all­vegetables­except ­­­­­­­-­­­­­­­­­­­­ asparagus,­beans,­spinach,

­­­­­­­­­­­­­­­­­­­­­­­­­­ cauliflower­­­­­­­­­­­­­­­­­­­­­­­­­­­ mushroom­max­50­g­per­day

fruit­­­­ ­­­­­­­­­­­­­­all­fruit­is­available ­­­­­-

drinks­­­­­­­­­­­­­ tea,­coffee,­soda­ ­alcohol

spices­­­­­­­­ all­spices­is­available­­­­­­­­­­­­­­­­­­­ ­­­yeast

PREVENTION ATTACK

I. avoidance

a.­far­walkingb.­tight­shoesc.­long­period­of­drivingd.­repetitive/heavy­hand­worke.­physical­and­mentally­fatiguef.­emotional­stressg.­excessive­purineh.­alcohol­drinkingi.­long­term­of­diuretic­usej.­long­term­of­aspirin­use

II.­­­Weight­losing­diet­and­low­purine­intake­­ ­­­­­­­­­­(high­purine­in­gut,­sardine,­clamshell,­duck,­ yeast,­cauliflower,­etc)

III.­Daily­Allopurinol

IV.­­Life­time/long­term­Allopurinol­in:­­­­­­­

-­more­than­5­attacks­a­year­­­­­­­ -­tophy­existence­­­­­­­ -­renal­stone­existence­­­­­­­ -­urate-nephropathy­existence­­

V.­NSAID­or­Colchicine­availability

When The pasient need to When The pasient need to be consultbe consult

Do not ignore septic jointDo not ignore septic joint

• Fever before and during monoarthritis Fever before and during monoarthritis indicating septic arthritisindicating septic arthritis

• Persistent Monoarthritis (and fever) despite the Persistent Monoarthritis (and fever) despite the given NSAID or colchisine, indicating septic given NSAID or colchisine, indicating septic arthritis.arthritis.

• If there hesitation, septic arthritis therapy givenIf there hesitation, septic arthritis therapy given• Gout and septic arthritis may occur together!Gout and septic arthritis may occur together!

Signs of impaired renal function. Acute gout attack occurs very often and pain is unmanageable pain If etiology is uncorrected Multiple tophies and large tophy that tends to damage the joint or secondary infection

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