55° Congresso Nazionale SIGG
LA GOTTA: UNA MALATTIA MISCONOSCIUTA NELL’ANZIANO?
LO STATO DELL
’ARTE NELLA
DELL’ARTE
GESTIONE DELLA GOTTA
Marco A Cimmino
Clinica Reumatologica, DI.M.I.
UNIVERSITA’ DI GENOVA
[email protected]
WHY IS GOUT OF PARTICULAR IMPORT IN
PRESENT TIMES?
• Frequency
• Changing clinical spectrum (more women,
more old aged, more often the upper limb)
• Metabolic implications
• Underdiagnosis and undertreatment
• New mechanisms (inflammasome, IL‐1)
• New treatments (anti IL‐1, febuxostat,
uricase)
• Potential usefulness of imaging
2
INFLAMMATION
DAMAGE
Asymptomatic hyperuricaemia
Acute intermittent attacks
Chronic tophaceous gout
INFLAMMATION
DAMAGE
Asymptomatic hyperuricaemia
?
Acute intermittent attacks
Chronic tophaceous gout
Criteri ACR per la diagnosi di artrite gottosa:
1.
Presence of monosodium urate crystals in synovial fluid AND/OR
2.
Tophus that contains urate crystals by chemical or polarized light
microscopy AND/OR
The presence of six of the following:
a. One attack of acute arthritis
b. Maximal inflammation occurring within one day
c. Attack of monoarticular arthritis
d. Presence of joint redness
e. First metatarsophalangeal joint painful or swollen
f. Unilateral attack involving first metatarsophalangeal joint
g. Unilateral attack involving tarsal joint
h. Suspected tophus
i. Hyperuricemia
j. Radiographic evidence of joint swelling
k. Radiographic evidence of subcortical cysts without erosions
l. Negative synovial fluid culture during acute attack
3.
4
Radiologo di 50 anni con iperuricemia asintomatica da almeno 20 e recente riscontro
di nodulo artrosico dell’interfalangea distale del 5° dito. Mai attacchi acuti, non
dolorabilità locale.
5
*
*
In corso di iperuricemia si può verificare un danno articolare
cronico asintomatico con lesioni anatomiche erosive
7/2007
artrite acuta
10/2007
2/2008
remissione
colchicina
Uomo di 43 anni con una storia di gotta da 6 anni, che ha presentato una artrite
oligoarticolare interessante anche il polso per la prima volta a luglio 2007
INFLAMMATION
DAMAGE
Asymptomatic hyperuricaemia
Acute intermittent attacks
Chronic tophaceous gout
INFLAMMATION
DAMAGE
Asymptomatic hyperuricaemia
US?
MRI?
wrist?
Tendons?
Acute intermittent attacks
Asymptomatic hyperuricaemia
Asymptomatic gout
Chronic tophaceous gout
COME COMPORTARSI DI FRONTE AD
UN PAZIENTE GOTTOSO
•
•
•
•
Terapia dell’artrite gottosa acuta
Suggerimenti di stile di vita
Terapia della gotta cronica
Profilassi degli attacchi acuti
Asymptomatic hyperuricaemia
Acute intermittent attacks
Chronic tophaceous gout
9
Treatment options during acute attack
Considerations
Nonpharmacological
• Rest
Colchicine
• Caution with renal or hepatobiliary dysfunction,
active infection
Chronic use complications
• Cold packs
• GI toxicity
• Drug interactions
• Can cause diarrhoea, GI upset with high doses
• IV colchicine should not be used
NSAIDs or
coxibs
• Ulcer disease, GI bleeds, NSAID-induced asthma or
renal dysfunction
• Potential for serious side
effects
• Interaction with warfarin
Corticosteroids
(systemic and
i.a.)
• No relevant side effects in acute use
• Hypertension
• Hyperglycaemia
• Osteoporosis
Anakinra
IPOURICEMIZZANTI?
10
Treatment options during acute attack
Considerations
Nonpharmacological
• Rest
Colchicine
• Caution with renal or hepatobiliary dysfunction,
active infection
Chronic use complications
• Cold packs
• GI toxicity
• Drug interactions
• Can cause diarrhoea, GI upset with high doses
• IV colchicine should not be used
NSAIDs or
coxibs
• Ulcer disease, GI bleeds, NSAID-induced asthma or
renal dysfunction
• Potential for serious side
effects
• Interaction with warfarin
Corticosteroids
(systemic and
i.a.)
• No relevant side effects in acute use
• Hypertension
• Hyperglycaemia
• Osteoporosis
Anakinra
IPOURICEMIZZANTI?
10
Arthritis
Arthritis Rheum
Rheum 2010;
2010; 62:
62: 1060‐8
1060‐8
11
Lifestyle changes recommended in gout
•
•
•
•
•
Diet
– Reduce purine intake (reduce red meat, butter, avoid liver, kidneys,
shellfish and pulses “Hülsenfrüchte”)
– Reduce fructose‐containing drinks
– Include skimmed milk, low fat yoghurt, vegetable protein and cherries
every day, vitamin C rich food
Decrease alcohol consumption (especially beer)
Weight loss
– 1 kg/month (avoid crash diets)
– Avoid high protein diets
Patients with urolithiasis should be encouraged to drink >2 L of water/day
Moderate exercise
Lifestyle changes have only modest effects on sUA
(eg 10‐15% reduction with a low‐purine diet), hence drug
therapy is usually required
12
Choi
Choi HK,
HK, Curhan
Curhan G.
G. Curr
Curr Opin
Opin Rheumatol
Rheumatol 2005;
2005; 17:
17: 341‐5
341‐5
Choi
HK,
et
al.
Lancet
2004;
363:
1277‐1281
Choi HK, et al. Lancet 2004; 363: 1277‐1281
Choi
Choi HK,
HK, et
et al.
al. N
N Eng
Eng JJ Med
Med 2004;
2004; 350:
350: 1093‐1103
1093‐1103
13
Induction of acute gouty arthritis by intra‐articular
injection of MSU + free fatty acids C18:0.
Inflammation dependent on ASC and caspase‐1, but not on NLRP3
Joosten
Joosten et
et al.
al. Arthritis
Arthritis Rheum
Rheum 2010;
2010; 62:
62: 3237–48
3237–48
14
Ann
Ann Rheum
Rheum Dis
Dis 2010;
2010; 69:
69: 766‐9
766‐9
Ann
Ann Rheum
Rheum Dis
Dis 2010;
2010; 69:
69: 1677‐82
1677‐82
16
EVIDENZA DELL’UTILITA’ DI DIMINUIRE
L’URICEMIA
Una uricemia inferiore a 5 mg/dL determina:
• Scomparsa o diminuzione degli attacchi acuti
– Becker at al (Arthritis Rheum, 2004)
• Meno cristalli nelle articolazioni
Urate solubility at:
– LiYu et al (J Rheumatol, 2001)
• Riduzione del volume dei tofi
– Perez Ruiz et al (Arthritis Rheum, 2002)
• Assenza di recidive dei depositi tofacei
– Gast et al (Clin Rheumatol, 2000)
% incidence of recurrent gouty
attack more than 1 year after
each patient’s first visit
35oC
37oC
100%
Observed
Logistic regression
80%
60%
40%
20%
0%
0.30 (5)
0.36 (6)
0.42 (7)
0.48 (8)
0.54 (9)
0.60 (10)
Average serum urate level during the whole investigation
period in mmol/L (mg/dL)
Shoji A, et al. Arthritis Rheum. 2004; 51(3):321‐325.
17
TERAPIA IPOURICEMIZZANTE
• Allopurinolo
– Dosaggio fino a 900
mg!
se non efficace, causa di effetti
collaterali, o in pazienti difficili
• Febuxostat
• Sulfinpirazone
– off label
• Uricase
18
Differences Between Febuxostat and Allopurinol
Febuxostat
Allopurinol
Chemical structure
and activity
Non-purine, selective
inhibitor of xanthine
oxidase
Purine, nonselective
inhibitor of xanthine
oxidase
Efficacy
Effective at
achieving <6 mg/dL
(<0.36 mmol/L)
Less effective at
achieving <6 mg/dL
(<0.36 mmol/L)
Excretion
Primarily eliminated
through the liver*
Primarily eliminated
through the kidney
Dosing
Effective at the lowest
dose (80 mg)
Needs to be titrated up
(from 100 mg)
Dosing in
renal insufficiency
Safe at standard doses
Dosage adjustment
required
*No dosage adjustments required in mild‐to‐moderate hepatic impairment.
19
Phase II Dose‐Response Study
TMX‐00‐004
Proportion of Subjects With sUA <6 mg/dL (<0.36 mmol/L) at Final Visit
*
94%
100
*
76%
% of Subjects
80
*
56%
60
40
20
*p<0.001 vs placebo
0%
0
Placebo
(N=35)
40 mg
(N=34)
Becker
Becker MA,
MA, et
et al.
al. Arthritis
Arthritis Rheum.
Rheum. 2005;
2005; 52:
52: 916‐923.
916‐923.
80 mg
(N=37)
120 mg
(N=34)
20
Schumacher
Schumacher HR,
HR, et
et al.
al. Arthritis
Arthritis Rheum
Rheum 2008;
2008; 59:
59: 1540‐8.
1540‐8.
21
PEGLOTICASE TREATMENT IN GOUT
Baraf
Baraf HSB
HSB et
et al.
al. Arthritis
Arthritis Rheum
Rheum 2008;
2008; 58:
58: 3632‐4
3632‐4
22
Colchicine for prophylaxis
• Colchicine prophylaxis during initiation of ULT for chronic gout:
– Reduces the frequency and severity of acute flares
– Reduces the likelihood of recurrent flares
– Evidence supports the use of low dose colchicine for up to for 6 months following
initiation of urate‐lowering therapy
Borstad
Borstad GC,
GC, et
et al.
al. JJ Rheumatol.
Rheumatol. 2004;
2004; 31(12):2429‐2432.
31(12):2429‐2432.
23
Harrod
Harrod LR,
LR, et
et al.
al. Arthritis
Arthritis Res
Res Ther
Ther 2009;
2009; 11R46
11R46
24
GLI IPERURICEMICI SONO PIU’
INTELLIGENTI?
Acido urico tipico dei primati tra i mammiferi
Possibile stimolante corticale
Numerosi uomini famosi della storia erano gottosi
JAMA
JAMA 1966;
1966; 195:
195: 415‐8
415‐8
25