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