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 ? La diagnosi precoce è possibile Comorbidità Effetti collaterali dei farmaci Conclusione

La diagnosi precoce è possibile oggi

Course of Rheumatoid Arthritis: Schematic Representation Inflammation Disability Radiographs (arbitrary units) Severity 5 10 15 20 25 30 Duration of disease (years) Kirwan JR. J Rheumatol. 1999;26:720-725.

EROSIONI OSSEE NEL 75% DEI PAZIENTI CON ARTRITE REUMATOIDE PRECOCE 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… 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; 3 articolazioni tumefatte Coinvolgimento delle MTF/MCF- test della gronda positivo 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… La diagnosi deve essere formulata nella fase precoce dell’AR entro i primi 3 mesi di malattia 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 objectives Prevention / arrest of joint damage Prevention / reversal of disability Sustained Remission Prevention of systemic co-morbidities: CV diseases, osteoporosis…. La rémission (disparition des symptômes et surtout arrêt de progression de la maladie = prévention des destructions ostéo-articulaires irréversibles) est aujourd’hui un objectif réaliste grâce aux nouvelles stratégies thérapeutiques (2-3-4) Les objectifs des traitements Faire disparaître les signes d’activité de la maladie Signes cliniques Syndrome inflammatoire biologique : VS, CRP Eviter ou du moins ralentir les destructions articulaires Evolution radiologique Prévenir les complications extra-articulaires Maintenir les fonctions articulaires et préserver la qualité de vie

Comorbidità

Comorbidità Comorbidities in rheumatoid arthritis Depression Glaucoma Renal disease Osteoporosis Comorbidità Cataract Infection Malignancy Easy bruising Anemia Gastrointestinal disease Diabetes Neurological manifestations Pancreatitis Lung involvement 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)

LIPID PROFILE DISEASE ACTIVITY TREATMENT LIPID PROFILE DISEASE ACTIVITY

Inflammation Autoimmunity  HDL 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

Rheumatoid arthritis Apo-AI Apo-B Apo-B / ApoAI ratio

CV risk? Inflammation degree INFLAMMATION AND LIPID INTERACTION IN RHEUMATOID ARTHRITIS Drug effects Inflammation degree Complexity of lipid evaluation CV risk?

Hydroxychloroquine Use Associated With Improvement in Lipid Profiles in Rheumatoid Arthritis Patients LDL (mg/dl) HDL (mg /dl) Total cholesterol (mg/dl) Triglycerides (mg/dl) LDL/HDL Chol/HDL 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, ,elevated cholesterol, RF status, and erosions van Halm VP,et al. ACR

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

Treatment effect DYSLIPIDAEMIA INDUCED BY INFLAMMATION Triglycerides IL-6 TNF-α LIVER Treatment effect CRP Total cholesterol HDL Triglycerides Small dense LDL ApoB/ApoAI Total cholesterol HDL Triglycerides Small dense LDL ApoB/ApoAI

Effetti collaterali della terapia

Risk factors of serious Infections 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 [OP0013] NO INCREASE IN OVERALL RISK FOR CANCER IN RA TREATED WITH TNF-ANTAGONISTS, BUT RISKS FOR CERTAIN CANCER TYPES MAY BE ELEVATED J. Askling 1, for the ARTIS Study Group 2 1Dept of Rheumatology, Karolinska University Hospital, Stockholm, 2Sweden Background: The occurrence of cancer following treatment with TNF-antagonists is not well understood. Whereas analyses of randomized trials suggest the possibility of an early and marked increase in the occurrence of several cancer types, observational studies have typically not been able to detect any increased overall cancer risk, although excess risks of certain types of cancer have been reported. Systematic or inadvertent screening before start of TNF-antagonist treatment may have excluded individuals with incipient cancer. By contrast, the direct effects of TNF-antagonist treatment might unmask incipient malignancies. It follows that only long-term assessments of cancer risk will allow an unbiased assessment of the full cancer occurrence associated with TNF-antagonists. Objectives: To assess the cancer occurrence in RA treated with TNF-antagonists Methods: Using the Swedish Biologics Register (ARTIS), pre-existing RA-cohorts, and matched individuals from the general Swedish population, we created three cohorts of (i) all 5,401 RA-patients starting TNF-antagonist treatment 1998 until 2005, (ii) 67,094 contemporary comparator RA-patients, and (iii) a matched general population cohort of 470,311 subjects. All unique individuals were followed for vital status 1998 until 2005 through national registers, and for malignancies through linkage to the Swedish Cancer Register (the mandatory Swedish notification system for malignancies) 1998 until 2005. Through stratified (age, sex, county, calendar year) and adjusted (four co-morbidities and joint surgery) Cox-regressions, the overall and site-specific occurrence of first primary cancers following RA-treatment with TNF-antagonists was compared to that of other RA, and to that of the general population. Results: Compared to the general population comparator (23,827 cancers, 2,650,119 person-years), the cancer occurrence in the RA cohort treated with TNF-antagonists (129 cancers whereof 114 first primaries during 14,261 person-years) corresponded to a relative risk of 1.07 (95% CI 0.74-1.29), and the cancer occurrence in the RA cohort not treated with TNF-antagonists corresponded to a relative risk of 1.09 (1.06-1.24). The adjusted relative risk comparing RA patients treated vs. not treated with TNF-antagonists was 0.93 (0.76-1.13), which included a transient drop in cancer risk in the TNF-antagonist treated group 1-3 years after first treatment start: RR < 1 year since first treatment start = 0.90 (0.64-1.27), RR 1 to 3 years since first treatment start = 0.62 (0.38-0.99), and RR 3 or more years since first treatment start = 1.06 (0.81-1.38). When site-specific cancer risks were assessed, RA treated (vs. not treated) with TNF-antagonists was associated with a reduced risk of breast cancer (RR=0.48, 95% 0.28-0.84). Non-significant increased risks were observed for colorectal (RR=1.52, 95% 0.85-2.78, n=14), for non-melanoma skin (RR=1.55, 95% 0.76-3.15, n=10), and for CNS (RR=2.25, 95%0.81-6.25, n=5) cancers. Conclusion: The overall cancer risk in RA-patients treated with TNF-antagonists is not higher than that among biologics-naïve RA-patients, and both these risks are largely similar to that of the cancer occurrence in the general population. The increased occurrence of non-melanoma skin cancer, of CNS tumours, and of colorectal cancer, although statistically strictly not significant and based on small numbers, needs further monitoring. Askling J, et al EULAR 2007, Barcelona, #OP0013 38

Increased risk of lymphoma in RA Swedish matched case control study Cases no.(%) Controls no.(%) Unadjusted OR no.(%)* Inflammatory activity† Low Medium High 94 (25) 196 (52) 86 (23) 278 (74) 4 (1) 1 (referent) 7.7 (4.8-12.3) 71.3 (24.1-211.4) Functional class‡ I II III IV 34 (9) 185 (49) 105 (28) 52 (14) 138 (37) 204 (54) 31 (8) 3 (1) 3.9 (2.4-6.3) 13.8 (7.2-26.2) 67.5 (18.9-239.8) † 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 RA patients have an increased risk of lymphoma, particularly if they have severe disease. Standard non-biologic treatments do not increase this underlying lymphoma risk. The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. After that, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1–28.0], OR tenth decile 61.6 [95% confidence interval 21.0–181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. EBV was present in 12% of lymphomas. The data shows results from 376 patients with RA complicated by malignant lymphoma and 376 matched controls. Reference Baeklund E, et al. Arthritis Rheum 2006;54:692-701 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 39

Conclusioni Diagnosi precoce Valutazione delle comorbidità Bilanciamento terapia Attenzione alle infezioni Attenzione alla possibile evoluzione neoplastica