Artrite reumatoide oggi: cosa è importante sapere per il MMG M Matucci Cerinic SOD Reumatologia AOUC Università di Firenze Cosa è importante sapere per il MMG ? 1. 2. 3. 4. La diagnosi precoce è possibile Comorbidità Effetti collaterali dei farmaci Conclusione La diagnosi precoce è possibile oggi Course of Rheumatoid Arthritis: Schematic Representation Severity (arbitrary units) Inflammation Disability Radiographs 0 5 10 15 20 Duration of disease (years) Kirwan JR. J Rheumatol. 1999;26:720-725. 25 30 DANNO ARTICOLARE NELLA ARTRITE REUMATOIDE E’ PRECOCE EROSIONI OSSEE NEL 75% DEI PAZIENTI CON ARTRITE REUMATOIDE PRECOCE Arthritis Rheum. 2002 feb. Artrite Reumatoide, inabilità al lavoro… % abilità al lavoro Anni di malattia I problemi del lavoro nella AR Il 10% dei pazienti con AR smette di lavorare entro 1 anno dalla diagnosi Il 50% smette di lavorare entro 10 anni dalla diagnosi Il 60% smette di lavorare entro 15 anni dalla diagnosi Il 90% abbandona il lavoro entro 30 anni dalla diagnosi Yelin E et al, Arthritis Rheum 30:507–512, 1987 RHEUMATOID ARTHRITIS Economic Burden (Europe) – In West Germany, the costs of RA were >40 billion DM (US $17.6 billion) in 1994 for treatment alone – In the UK, average RA outpatient cost/case/year was £798 (US $1,126) and £1,253 (US $1,769) per inpatient in 1997 – RA per capita costs average: • • • • 49% of cost of cancer 68% of cost of stroke 82% of cost of coronary heart disease 5X cost of motor vehicle accidents Knorr U. Versicherungsmedizin. 1994. Rothfuss J. Akt Rheumatol. 1997. Lubeck DP et al. Arthritis Rheum. 1986;29:488–493. Lorig KR et al. Arthritis Rheum. 1993;36:439–446. Costi dell’AR • Diretti: 380 mil Euro Spese ricoveri, farmaci, acertamenti diagnostici, visite (a carico paz e SSN) • Indiretti: 1210 mil Euro spese sostenute dalla collettività, mancati guadagni dovuti a invalidità Costi Complessivi 1600 mil Euro Costi Ombra: a carico del malato e suoi familiari per far fronte alla malattia Difficilmente quantizzabili, si aggirano all’incirca attorno ad un MILIARDO di Euro Obiettivi del trattamento dell’AR Alleviare i sintomi Conservare la funzionalità Prevenire il danno strutturale e le deformità Mantenere o recuperare il normale stile di vita del paziente Sicurezza a lungo termine Akil M, Amos RS, BMJ 310:587–590, 1995 AR Precoce il medico di medicina generale od altro specialista deve sospettare una artrite in fase precoce ed inviare il paziente al reumatologo quando osserva; 1. 3 2. articolazioni tumefatte Coinvolgimento delle MTF/MCFtest della gronda positivo 3. Rigidità mattutina 30 minuti DANNO ARTICOLARE NELLA ARTRITE REUMATOIDE E’ PRECOCE • Il danno inizia entro i primi tre mesi • Entro i primi tre mesi è necessaria la diagnosi STRATEGIA TERAPEUTICA ATTUALE TRATTAMENTO AGGRESSIVO NELLE PRIME FASI ( primi 3 mesi ) E’ oggi possibile ottenere una diagnosi più precoce di AR con l’aiuto di parametri clinici di laboratorio, genetici, e di diagnostica per immagini di vario tipo che abbiano un valore predittivo. …dobbiamo evitare che l’ansia di una ricerca di diagnosi molto precoce vada a scapito di un corretto inquadramento diagnostico e di un corretto approccio terapeutico… (S. Bombardieri - SIR 2006) Dogmi… 1. La diagnosi deve essere formulata nella fase precoce dell’AR entro i primi 3 mesi di malattia 2. La diagnosi deve essere formulata e la terapia iniziata prima che abbia inizio le erosioni che danneggino in maniera irreversibile le articolazioni e la loro funzione. Management of patients with RA, Therapeutic Sustained Remission Prevention / reversal of disability objectives Prevention / arrest of joint damage Prevention of systemic co-morbidities: CV diseases, osteoporosis…. Comorbidità Comorbidities in rheumatoid arthritis Glaucoma Depression Renal disease Osteoporosis Comorbidità Cataract Infection Anemia Malignancy Gastrointestinal disease Pancreatitis Easy bruising Diabetes Lung involvement Neurological manifestations Cardiovascular disease Cardiovascular risk factors in rheumatoid arthritis (RA) Traditional risk factors Age BMI Dyslipidemia Hypertension Diabetes mellitus Smoking Family hystory Sedentary life style Homocysteine Insulin-resistance RA-related risk factors Inflammation-mediated Adhesion molecules (VCAM-1 / ICAM-1) Proinflammatory cytokines (TNF-α, IL-1, IL-6) C-reactive protein MCP-1 Immune-mediated Rheumatoid factor Anti-CCP ACL anti-oxLDL CD4+CD28null T cells Oxidative stress (oxLDL, proinflamm. HDL) Endothelial progenitor cells (EPC) TREATMENT LIPID PROFILE DISEASE ACTIVITY Inflammation Autoimmunity Jick, ARD 2009;68:546 Choy, ARD 2009;68:460 Gerli, Arthritis Care Res 2010;62:712 Myasoedova, ARD 2011;70:482 Bartels, Arthritis Rheum 2011;63:1221 HDL Rheumatoid arthritis Apo-AI Apo-B Apo-B / ApoAI ratio INFLAMMATION AND LIPID INTERACTION IN RHEUMATOID ARTHRITIS Inflammation degree Complexity of lipid evaluation Drug effects Hydroxychloroquine Use Associated With Improvement in Lipid Profiles in Rheumatoid Arthritis Patients LDL (mg/dl) LDL/HDL HDL (mg /dl) Chol/HDL Total cholesterol (mg/dl) Triglycerides (mg/dl) Morris S et al. Arthritis Care Res 2011;4:530-4 Anti-RA drugs decrease CV risk • Case control study • 72 with history of CV events; 541 without history of CV events • All patients anti-TNF-naïve • Analysis: Corrections for age, gender, smoking, RA duration HTN, DM, 0,35 0,3 0,25 0,2 0,15 0,16 0,16 0,11 0,1 0,05 ,elevated cholesterol, 0 RF status, and erosions van Halm VP,et al. ACR 0,37 0,4 Risk for CV Event MTX only SSZ only MTX+SSZ Triple Effects of DMARDs on lipid levels in rheumatoid arthritis 42 RA patients treated with DMARDS (essentially MTX) for 12 months HDL cholesterol by 21% (p<0.001) apolipoprotein A-I by 23% (p<0.001) LDL/HDL cholesterol ratio (N.S.) Significant differences between responders and nonresponders in the mean 12-month changes in: HDL cholesterol apolipoprotein A-I LDL/HDL cholesterol ratio Park Y-B et al. Am J Med 2002;113:188-93 Effect of TNF inhibitors on lipid profile in RA: a systematic review with meta-analysis Daien CI et al. Ann Rheum Dis 2012;71:862-8 DYSLIPIDAEMIA INDUCED BY INFLAMMATION IL-6 TNF-α LIVER CRP Total cholesterol HDL Triglycerides Small dense LDL ApoB/ApoAI DYSLIPIDAEMIA INDUCED BY INFLAMMATION IL-6 TNF-α LIVER Treatment effect Total Totalcholesterol cholesterol HDL HDL Triglycerides Triglycerides Small Smalldense denseLDL LDL ApoB/ApoAI ApoB/ApoAI CRP Effetti collaterali della terapia Risk factors of serious adverse events in RA Risk factors of serious Infections Age (≥ 60,≥≥ 80) Previous serious infection (in the past year +) Corticosteroid use (dosage ) Elevated ESR Systemic manifestations Comorbidities (Coronary Heart Disease,Heart failure,peripheral vascular disease,chronic lung disease, diabetes, alcoholism) Biologics ? Crowson S et al Arthritis Rheum 2012;64: 2847-55. Curtis JR et al. Arthritis Rheum. 2007;56:112; Srangfeld A et al Ann Rhem Dise 2012;70 :1914-20 Predictors and Risk of Infection in Rheumatoid Arthritis Relative Risk to general population: 1.9 [1.7 – 2.1] Best predictors: RA severity / disease activity Age Corticosteroid therapy Comorbid diseases: CVD, CHF, CRF, DM, lung disease Previous infection Joint surgery Contributory role of DMARDs not clearly defined Moreland et al. J Rheum 2001;28:1238-44. Safety of biologics in patients with RA Serious infections: Rate from 2 to 8 / 100 patient-Years depending of the studies (RCTs vs registries), and patients populations Opportunistic infections including TB: Reported for all biologics Tb screening recommended for all biologics but RTX Malignancies and lymphomas: No signal Injection reactions Others: Transaminases, lipides, neutropenia Dixon W, et al. Arthritis Rheum 2006;54:2368-76; Weinblatt M et al Arthritis Rheum 2006;54:2807-16;Gottenberg J et al Arthritis Rheum. 2010 ;58: Mariette et al, Ann Rheum Dis. 2011;70:1895-904 ;Smolen J et al Ann Rheum dis 201o Cancers risk in RA Patients RA cohort (n=66 471) - 0.7% of Swedish population alive in 1998, identified in 3 overlapping national registers Followed through to 2005 Cancer in RA not treated with anti-TNF Relative risk of cancer All site, 3742 Respiratory tract, 410 Upper GI, liver, pancreas, 300 Colorectal, 329 Breast, 534 Ovary, Uterus, Cervix, 227 Prostate, Testes, 530 Kidney, Bladder, 253 Skin, melanoma, 115 Skin, non-melanoma, 306 Central nervous system, 72 Other, 279 1.11 (1.08, 1.16) 1.35 (1.21, 1.51) 1.12 (0.98, 1.27) 0.75 (0.67, 0.85) 0.94 (0.86, 1.03) 0.83 (0.72, 0.96) 1.06 (0.96, 1.16) 1.22 (1.06, 1.41) 1.14 (0.93, 1.40) 1.76 (1.54, 2.01) 1.09 (0.84, 1.41) 1.29 (1.12, 1.47) 0 1 2 3 4 Askling J, et al EULAR 2007, Barcelona, #OP0013 Increased risk of lymphoma in RA Swedish matched case control study Cases no.(%) Controls no.(%) Unadjusted OR no.(%)* Low 94 (25) 278 (74) 1 (referent) Medium 196 (52) 94 (25) 7.7 (4.8-12.3) High 86 (23) 4 (1) 71.3 (24.1-211.4) I 34 (9) 138 (37) 1 (referent) II 185 (49) 204 (54) 3.9 (2.4-6.3) III 105 (28) 31 (8) 13.8 (7.2-26.2) IV 52 (14) 3 (1) 67.5 (18.9-239.8) Inflammatory activity† Functional class‡ † Score reflecting the entire period from onset of rheumatoid arthritis (RA) until diagnosis of lymphoma, based on TJC, SJC, ESR, and PGA ‡ Steinbrocker criteria 1 year before lymphoma diagnosis Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease High inflammatory activity, rather than its treatment, is a major risk determinant 376 patients with RA complicated by malignant lymphoma and 376 matched controls Baeklund E, et al. Arthritis Rheum 2006;54:692-701 Conclusioni 1.Diagnosi precoce 2.Valutazione delle comorbidità 3.Bilanciamento terapia 4.Attenzione alle infezioni 5.Attenzione alla possibile evoluzione neoplastica