Breaking news nelle malattie reumatiche

Breaking news nelle
malattie reumatiche
Gianfranco Ferraccioli
Istituto di Reumatologia e
Scienze Affini - UCSC
Roma
Prevalence of rheumatic diseases:
2° place after hypertension
(58% age less than 65)
Age
Prevalence
http://www.phac-aspc.gc.ca/cd-mc/arthritis-arthrite/lwaic-vaaac-10/3-eng.php
Only few affect only joints:
the majority are FULL systemic ilnesses
1
4
5
2
3
Impact
Impact
(n° 401)
(n° 220)
(n° 506)
(n° 442)
Gremese E. et al.
(n°204)
Cardiovascular disease in patients with rheumatoid arthritis: results from the
QUEST-RA study ( Antonio Naranjo , Tuulikki Sokka, Miguel A Descalzo, Jaime Calvo-Alen , Kim Horslev-Petersen, Reijo K
Luukkainen , Bernard Combe, Gerd R Burmester Joe Devlin, Gianfranco Ferraccioli et.al. )Arthritis Research & Therapy 2008,
10:R30 doi:10.1186/ar2383
Cardiovascular morbidity
No
(percentage of patients)
Yes
Hazard ratio
95% CI
P value
Rheumatoid variables
Rheumatoid factor
0.881
71.7
77.0
1.02
0.76-1.37
Extra-articular disease
0.001
23.0
43.3
1.52
1.19-1.95
55.8
66.4
1.05
1.04-1.06
Traditional risk factors
Age in years (mean)
0.000
Gender (female)
79.4
64.0
0.42
0.33-0.54
0.000
Hypertension
28.7
62.9
2.97
2.31-3.83
0.000
Hyperlipidemia
11.3
34.0
3.19
2.47-4.13
0.000
Diabetes
6.9
15.8
2.09
1.50-2.92
0.000
Impact
Pharmacology of rheumatic
diseases
Breaking news in Rheumatic Diseases
• Breakthrough in RA
• Breaktrough in AS
• Breackthrough in PsA
Breaking news in RA: pathogenesis
Nature Clinical Practice Rheumatology (2007) 3, 336-345
Autoreactive B cells activate T cells
through IL6 , IL2 and IFNγ
SYK Inhibitors
BTK inhibitors
CD38 target
CD20 target
Rheumatoid arthritis pharmacotherapy
landscape: towards PRECISION MEDICINE
Breaking news in RA:
at least 10 therapeutics targets
Breaking news in RA:
early intervention
Very early rheumatoid arthritis as a predictor of remission: a
multicentre real life prospective study
E. Gremese, et al. Ann. Rheum. Dis. 2013, 72:858-862
Remission: this is the aim
Nat. Rev. Rheumatol. 11, 276–289 (2015),
Ann Rheum Dis 2015;74:19–26
Treat early….to stop soon
N Engl J Med 2014;371:1781-92.
PRIZE Trial
Treat early….to stop soon
N Engl J Med 2;371:1781-92.
44% of patients in Combo, 29 % of MTX and 23 % of placebo were still in remission
EARLY Treatment of RA
E EARLY DIAGNOSIS AND TREATMENT OF RA
A AGGRESSIVE USE OF DMARDS ALTERS THE COURSE OF RA
R REMISSION IS THE NEW TARGET OF RA TREATMENT
L LONG TERM USE OF DMARDS and or BIOLOGICS
YES, DMARDS ARE SAFE WHEN MONITORED REGULARLY
Y
This is the new standard of care.
Once Remission has been reached go for a drug-free phase.
Breaking news in SpA and PsA
1.Unmet needs in SpA
2.Unmet needs in PsA
1.New pathogenetic aknowledgements
1.Better therapeutics
SpA prevalence is even bigger than RA
Diagnosed patients (000s)
EU Countries*
1.880
1.423
~1.4%
~0.5%
1.197
Drug-treated (000s)
1.328
1.146
920
Biologic-treated (000s)
Fewer
Crowded
203
80
RA
* Germany, Italy, UK, France, Spain
Pso
mod-sev
156
SpA
Pathogenesis of sacroiliitis
Braun A&R 1995
SpA and PsA are chronic debilitating inflammatory diseases
with an high unmet medical need
SpA
Prevalence 1 to 1.4%
50% AS
Axial SpA
2/3
Peripheral SpA
1/3
new bone
formation in the
axial skeleton
50% PsA
Joint erosions within 1
year in 40% of patients
50% Non Radiographic Axial SpA
Up to 40% of patients do not achieve adequate disease control with anti-TNF1
•
Clinical practice perception
-
1/3 ‘good’ responders
-
1/3 ‘partial’ responders
-
1/3 non-responders (and/or intolerance)
2/3 of Pts have a suboptimal response
•
Efficacy may be lost over time2
•
Have not been shown to inhibit radiographic progression3,4
1. Wendling D, et al. Expert Opin Pharmacother 2004;5:1497–507; 2. Chang C, et al. Nat Rev Rheumatol. 2011;7:588–98;
3. van der Heijde D, et al. Arthritis Rheum. 2008;58:1324–31; 4. van der Heijde D, et al. Arthritis Rheum.22
2008;58:3063–70
Breaking news in the
pathogenesis of Psoriatic Arthritis
F1000Prime Reports 2014, 6:4
Breaking news in PsA and SpA:
The 12-IL-23/IL-17 pathway plays a central role in joint
inflammation, skin inflammation and enthesitis
IL-12 and
IL-23, activate T cells
Differentiation and
clonal expansion
of Th1 and Th17 subsets
is prevented
Th1
up-regulation
of inflammatory
cytokines
TNF-α
IFN-γ
T cell
Th17
TNF-α
IL-17
IL-22
1. Gately MK, et al. Annu Rev Immunol. 1998;16:495-521. 2. Wilson NJ, et al. Nat Immunol. 2007;8(9):9507. 3. Nickoloff BJ, Nestle FO. J Clin Invest. 2004;113(12):1664-75. 4. Nestle FO et al. J Invest Dermatol. 2004;
123:xiv-xxv.
IL17 is a key target in AS
Lancet 2013; 382: 1705–13
IL12/IL23 in CD
N Engl J Med 2012;367:1519-28.
Ustekinumab Induction and Maintenance Therapy in Refractory
Crohn’s Disease
William J. Sandborn et al.
Adult moderate, severe CD patients refractory to anti-TNF. The
primary end point was a clinical response at 6 weeks.
CD and PsA
• Psoriasis and CD occur more often in the same
person than it would be expected if the diseases
were mutually exclusive. Data from five case-control
studies reported a prevalence of psoriasis of 8.9% in
patients with CD, but only of 1.4% in the control
group ( 1 × 10−9) [Nair LP et al 1997 ].
• Lee et al. in 1990 reported an incidence of psoriasis
in patients with CD of 9.6%, while in the control
group it was only 2.2%. and incidence of psoriasis in
relatives of patients with CD of 10%, compared to
2.9% in the control group ( LE fi et al 1990, Nair LP et
al Bernstein CN 2005)
• The IL-23R has a fundamental pathogenetic role both
in IBD (IBD17) and in psoriasis (PSORS7)
IL12/23 in PSO
N Engl J Med 2010;362:118-28
Etanercept
Uste 45 mg
Uste 90 mg
IL12/IL23 in PsA
Ritchlin C, Rahman P, Kavanaugh A, et al.
Ann Rheum Dis 2014;73:990–999.
• Significant treatment differences were observed
for week 24 HAQ-DI improvement (p<0.001),
ACR50 (p≤0.05) and PASI75 (p<0.001)-Psummit2
Conclusions and take home messages
1. In RA , SpA and PsA, the new pathogenetic
targets have led to define new therapeutics that
allow to reach remission and even a temporary
drug free remission.
2. Only basic science identifying the new molecular
pathways can allow to reach major outcomes.
3. Biomarkers are badly needed to identify different
subsets of patients.
New perspectives
1. Biomarkers for subsets identification
2. Cellular immunophenotyping by
multiparameter single-cell analysis
(Science 2011,332,687–696)
3. > 34-marker masscytometry
4. Single cellRNA-seq
(Nat. Methods 2009, 6,377–382)
(Proc. Natl Acad. Sci. USA 2014,111,E2770)
Aknowledgements
•
•
•
•
•
•
•
•
E.Gremese
B.Tolusso
S.Bosello
G.Peluso
A.Zoli
L.Mirone
M.Lizzio
M.De Santis
Cattedra di Reumatologia
Laboratorio di Reumatologia
molecolare e cellulare
Facolta’ di Medicina
Universita’ Cattolica