La Terapia nelle Spondiloartriti
Carlo Salvarani,
Unità Operativa di Reumatologia,
Ospedale di Reggio Emilia
Terapia nelle SpA
„ SPONDILITE ANCHILOSANTE
„ ARTROPATIA PSORIASICA
Spondilite Anchilosante
La storia naturale della spondilite anchilosante: uno
studio prospettico
„
„
„
„
„
Studio prospettico di 150 veterani americani con SA iniziato
nel 1947
81 erano ancora vivi nel 1980 ed erano stati rivisti
periodicamente
51 /81 erano rivalutati (durata media SA: 38 anni)
21 (41%) progressione a severa limitazione della mobilità della
colonna
81% di questi 21 pts presentavano una severa limitazione già
nei primi 10 anni di malattia
Carrette et al, Arthr Rheum, 1983
The Natural Course of Radiographic Progression
in AS – Evidence for Major Individual Variations
in a Large Proportion of Patients
Baraliakos et al, J Rheumatol 2009 March 30 (Epub ahead of print)
„ Objective:
to describe the natural course of
radiographic progression
„ Methods: 146 patients with AS who had
never received TNF-blockers and had
complete sets of cervical and lumbar
radiographs from at least 2 timepoints
within 6 years
The Natural Course of Radiographic Progression
in AS – Evidence for Major Individual Variations
in a Large Proportion of Patients
Baraliakos et al, J Rheumatol 2009 March 30 (Epub ahead of print)
„ Results:
- 43% of patients showed a 4-fold greater rate
of progression than the mean
- 23% had no progression
- the number of syndesmophytes at baseline
predicted the radiographic progression
Spine x-rays
syndesmophytes
ASAS/EULAR Recommendations
for the Management of AS
Zochling et al, Ann Rheum Dis 2006
„ there is no evidence for the efficacy
of
disease modifying antireumatic drugs
(DMARDs), including sulfasalazine and
methotrexate, for the treatment of axial
disease. Sulfasalazine may be considered
in patients with peripheral arthritis
NELLA SPONDILITE ANCHILOSANTE VI E’
LA NECESSITA’ DI TRATTAMENTI:
- efficaci sulle manifestazioni assiali (e anche su
quelle periferiche e extra-articolari)
- in grado nel lungo termine di funzionare
come agenti modificanti la malattia
Malattia di Chron associata con SA
Efficacia della terapia anti-TNF con
infliximab in pazienti con malattia di
Crohn e sintomi articolari (n = 4)
Van den Bosch et al, Lancet 2000
Pathology – TNF and AS
„
Increased TNF serum levels in AS patients
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„
Gratacos J, et al. Br J Rheumatol 1994; 33:927-931
Increased TNF mRNA and protein in biopsy
specimens from inflamed SI joints of patients
with AS
„
Braun J et al, Arthritis Rheum 1995; 38(4):499-505
Adalimumab, etanercept and infliximab for the treatment of AS:
a systematic review and economic evaluation
McLeod C, et al. Health Technol Assess 2007; Review
„
„
The review of clinical data related to the 3 drugs
compared with conventional treatment plus placebo
indicates that in the short term (12-24 weeks), the 3
treatments are clinically effective in relation to
assessment of ASAS, BASDAI and BASFI
Indirect comparisons of treatments did not show a
significant difference in effectiveness between the 3
agents
Argomenti
„ Mantenimento dell’efficacia e sicurezza nel
trattamento prolungato anti-TNF
„ Cosa succede alla sospensione dell’agente
anti-TNF?
„ Sicurezza e efficacia della ripresa della
terapia anti-TNF
„ E’ la terapia anti-TNF in grado di inibire il
danno strutturale?
Mantenimento dell’efficacia nel
trattamento prolungato
Braun J et al. Persistent clinical efficacy and safety
of anti-TNFα therapy with infliximab in patients
with AS over 5 years – evidence for different types of
response. Ann Rheum Dis 2008
„ Davis Jr JC, et al. Efficacy and safety of up to 192
weeks of etanercept therapy in patients with AS.
Ann Rheum Dis 2008
„ van der Heijde D, et al. Adalimumab treatment
maintains efficacy and safety in patients with AS – 2
year results from ATLAS. Ann Rheum Dis 2008
„
Sicurezza nel lungo termine
„ Only 2
patients (4.6%) in infliximab therapy
discontinued the study for possibly drug-related
events (recurrent vaginal and upper respiratory
tract infections)
„ Only 4 patients (1.6%) during long-term
etanercept therapy had infections leading to
study withdrawal
„ Only 6 patients (1.9%) during long-term
adalimumab therapy had serious infections
leading to study withdrawal
Real life experience confirms sustained response
to long-term biologics and switching in AS
Coates et al, Rheumatology 2008
„ Treatment of active AS with TNF blockers
according to the BSR guidelines leads to a
sustained response for over 2 yrs with most
patients tolerating the drugs well
„ The rate of non-response is significantly lower
than that seen in RA and nearly all of these
patients respond well to a second-line agent
Cosa succede alla sospensione
della terapia anti-TNF?
„
Brandt J, et al. Six-month results of a doubleblind, placebo-controlled trial of etanercept
treatment in patients with active AS. Arthritis
Rheum 2003
„
Baraliakos X, et al. Clinical response to
discontinuation of anti-TNF therapy in patients
with AS after 3 years of continuous treatment with
infliximab. Arthritis Res Ther 2005
Cosa succede alla sospensione
della terapia anti-TNF?
„ comparsa di recidiva (incremento di almeno
2 nel BASDAI) nel 75% dei pazienti entro 3
mesi dalla sospensione di etanercept (media
6 settimane)
„ recidiva di malattia più tardiva nel restante
25% dei pazienti
Brandt J et al, Arthritis Rheum 2003
Cosa succede alla sospensione
della terapia anti-TNF?
„
Il 98% dei pazienti con SA che sospendevano
infliximab dopo 3 anni di terapia continuativa
avevano un recidiva (BASDAI > 4) entro 52
settimane dalla sospensione e dovevano essere
ritrattati
„
Il tempo medio di recidiva dalla sospensione della
terapia era 17,5 settimane
Baraliakos X et al, Arthritis Res Ther 2005
Sicurezza e efficacia della ripresa
della terapia anti-TNF
„ Dopo
24 e 48 settimane di risomministrazione di infliximab i valori di BASDAI
erano simili ai quelli di prima della
sospensione
„ La incidenza globale di effetti collaterali era
simile a quella dei primi 3 anni di terapia
negli stessi pazienti
Baraliakos X et al, J Rheumatol 2007
TNF-blockers and MRI in AS
Adalimumab, etanercept and infliximab
significantly reduce both spinal and SI joint
inflammation in patients with active AS,
and these improvements are maintained
during the treatment
Lambert, et al. Arthritis Rheum 2007
Marzo-Ortega H, et al. Arthritis Rheum 2001
Braun J, et al. Arthritis Rheum 2003
E’ in grado il trattamento continuativo di ridurre o
bloccare il danno strutturale (evoluzione radiologica)
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Baraliakos X, et al. Outcome of patients with active AS
after 2 years of therapy with etanercept: clinical and MRI
data. Arthritis Rheum 2005
Van der Heijde D, et al. Two-year etanercept therapy
does not inhibit radiographic progression in patients with
AS. Ann Rheum Dis 2006
Baraliakos X, et al. Radiographic progression in patients
with AS after 4 yrs of treatment with anti-TNF-α antibody
infliximab. Rheumatology 2007
Van der Heijde D, et al. Radiographic findings following
two years of infliximab therapy in patients with AS.
Arthritis Rheum 2008
E’ in grado il trattamento continuativo di ridurre o bloccare
il danno strutturale (evoluzione radiologica)
„
MRI evaluation showed a 75% improvement of active
spinal lesions, but minor spinal inflammation was still
present in 64% of patients after 2 years of therapy with
etanercept
„
Whereas clinical findings demonstrate sustained, durable
benefits with long-term (2 years) etanercept therapy, x ray
evaluations (cervical and lumbar spine scored with
mSASSS) suggest that progression of structural damage
continued
Baraliakos X, et al. Arthritis Rheum 2005
Van der Heijde D, et al. Ann Rheum Dis 2006
E’ in grado il trattamento continuativo di ridurre o bloccare
il danno strutturale (evoluzione radiologica)
„
„
There is some radiographic progression after 2 and 4 years of
infliximab therapy in AS patients (cervical and lumbar spine
scored with mSASSS)
AS patients who received infliximab from baseline through
week 96 did not show a statistically significant difference in
inhibition of structural damage progression at year 2, as
assessed using the mSASSS scoring system, when compared
with radiographic data from the historical control OASIS
cohort
Baraliakos X, et al. Rheumatology 2007
Van der Heijde D, et al. Arthritis Rheum 2008
AS and RA: TNF-blocker therapy and
radiographic progression
„
„
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In RA the proinflammatory effects of TNF coincide
with osteoclast activation and subsequent bone erosion
In RA there is a clear longitudinal relationship between
clinical disease activity and subsequent radiographic
damage
The hallmark of AS is bone formation rather than bone
resorption
Schett G et al. Ann Rheum Dis 2007;
Welsin PM et al. Arthritis Rheum 2004;
Van der Heijde D et al, Arthritis Rheum 2008
AS and RA: TNF-blocker therapy and
radiographic progression
„ Structural
progression in AS seems to be
independent of TNF, despite the fact TNF is
responsible for inflammatory signs/symptoms
„ In AS there is no relationship between
radiographic progression and clinical disease
activity
Schett G et al. Ann Rheum Dis 2007;
Welsin PM et al. Arthritis Rheum 2004;
Van der Heijde D et al, Arthritis Rheum 2008
Possible Explanations for the Lack of TNF-blockers
Efficacy on Radiographic Progression in AS
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The average disease duration of TNF-blockers
treated AS patients in the studies was ~ 10 years
Earlier intervention in the disease process, before
the reparative processes have started, could prevent
further bone formation
Inflammation would have to be suppressed for a
longer period of time before the inhibitory effects
can be seen on radiographs
Van der Heijde et al, Arthritis Rheum 2008
Artrite Psoriasica
TERAPIA DELL
’ARTROPATIA PSORIASICA
DELL’ARTROPATIA
l’AP non è una malattia più lieve della AR:
„
„
40% dei pts ha una malattia erosiva e deformante
in uno studio della durata di 5 anni la frequenza dei
pts con danno radiologico in 5 o più articolazioni
passava dal 19% al 41%, nonostante la riduzione della
VES e del numero delle articolazioni
dolenti/tumefatte
Gladman et al, Q J Med 1987 and J Rheumatol 1990
TERAPIA DELL
’ARTROPATIA PSORIASICA
DELL’ARTROPATIA
l’AP non è una malattia più lieve della AR:
„
Utilizzando il metodo di Steinbroker modificato
la severità radiologica dei pazienti con AR era
simile a quella dei pazienti con AP quando
venivano comparati pazienti di età, sesso e
durata di malattia uguale
Rahman et al, J Rheumatol 2001
A prospective, clinical and radiological study
of early PsA: an early synovitis clinic experience
Kane et al, Rheumatology 2003
„
„
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Objective: to determine the clinical presentation
and clinical and radiological outcome of early PsA
(disease duration < 2 years) at 1 and 2 years
Despite clinical improvement with current
DMARDs, PsA resulted in radiological damage in
up to 47% of patients at a median interval of 2
years
PsA is a chronic, progressive disease in the
majority of patients
Terapia dell’artropatia psoriasica
„
i DMARDs tradizionali controllano i sintomi, ma
non vi sono dimostrazioni che siano in grado di
inibire il danno articolare strutturale
„
Gli agenti anti-TNFα riducono i segni/sintomi,
migliorano lo stato funzionale e la qualità della
vita e inibiscono la progressione del danno
strutturale nell’artrite periferica
Risks and benefits of TNF-α inhibitors in the management
of PsA: systematic review and metaanalysis of RCTs
Saad AA, et al. J Rheumatol 2008
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6 RCT (982 patients) of adalimumab, etanercept, and
infliximab used in PsA patients were identified
All 3 drugs were significantly more effective than placebo on
the basis of PsARC, ACR20, ACR50, and ACR70
All 3 drugs blocked radiographic progression
All 3 drugs were shown to be equally effective in the
treatment of PsA
There was no differences between these 3 drugs and placebo
in the proportions of patients experiencing withdrawal for
any reason or due to adeverse events, and serious adverse
events
Mease PJ et al. ADEPT 1699 # A25 S. Diego ACR 2005
Mean Change in mTSS
Mean change in mTSS through Week 48
1,5
Placebo eow
Adalimumab 40 mg eow
1
0,5
*
0
-0,5
0
Placebo
Adalimumab
24
N
Baseline
Week 24 mean
change
141
133
22.1
23.4
0.9
–0.1
*p<0.001, adalimumab (Week 48) vs placebo (Week 24)
48
Week 48 mean
change
1.0
0.1
Cost-effectiveness of etanercept and adalimumab
in psoriatic arthritis: the Italian studies
„
adalimumab appears to be cost effective for the
treatment of PsA
Eandi and Salvarani, Farmeconomia e percorsi terapeutici 2006
„
TNF antagonists (mainly etanercept) provide “value”
and “value for money” in the treatment of PsA in
clinical practice
Olivieri et al, Rheumatology 2008
Frequency and duration of clinical remission in patients with
peripheral psoriatic arthritis requiring second-line drugs
Cantini F et al, Rheumatology 2008
„
Remission is possible in up to 24% of patients with
peripheral PsA
„
It is significantly more frequent, but not longer, in patients
receiving anti-TNF drugs compared with those treated
with traditional DMARDs
„
Patients remain in remission for a long period after therapy
interruption, thus suggesting an intermittent therapeutic
strategy
Systematic review of treatments for
psoriatic arthritis: an evidence based
approach and basis for treatment
guidelines
Kavanaugh AF, Ritchlin CT, and the
GRAPPA Treatment Guideline Committee
J Rheumatol 2006; 33:1417-21
PsA: management
Diagnosis
Monoarthritis
Tenosyinovitis
Local therapy
NSAIDs
Low-dose CS
Asymmetric
Oligoarthritis
Local therapy
NSAIDs
Low-dose CS
≥5 joints
>ESR
PsA
spondylitis
DMARDs
ASAS
guidelines
Nonresponders
PsA: traditional DMARDs therapy
DMARD
PARENTERAL GOLD
RETINOIDS
ANTIMALARIAL AGENTS
SULFASALAZINE
METHOTREXATE
CYCLOSPORIN A
LEFLUNOMIDE
Meta
-analisi dei trials controllati e randomizzati per
Meta-analisi
valutare ll’efficacia
’efficacia e la tossicit
à delle terapie della AP
tossicità
„
„
„
le due sole terapia di dimostrata efficacia erano
la sulfasalazina e le alte dosi di metotressato
le basse dosi di metotressato e l’etretinato
potrebbero essere efficaci, però i dati
disponibili sono insufficienti
miglioramento anche del gruppo trattato con
placebo
Jones et al, Br J Rheumatol 1997
Parenteral gold, Retinoids, Antimalarials
9Parenteral Gold: no evidence of efficacy on
arthritis, psoriasis worsening
Gladman DD, Semin Arthritis Rheum 2003
9Chloroquine, Hydroxychloroquine: no
efficacy
Gladman DD, et al. J Rheumatol 1992
9Retinoids: efficacy on psoriasis, slight
efficacy on arthritis, frequent AEs
Klinkhoff AV, et al. J Rheumatol 1989
TERAPIA CON SSZ NELLA AP
„
„
in 6 studi randomizzati, doppio cieco, placebocontrollati la sulfasalazina era superiore al
placebo nella terapia della AP
in uno studio su 221 pts con AP la risposta al
trattamento era del 57,8% nel gruppo trattato
con SSZ e del 44,6% nel gruppo placebo (p =
0,05)
Clegg et al, Arthritis Rheum 1996
TERAPIA CON SSZ NELLA AP
„
mentre la SSZ è efficace nell’artrite
periferica, non lo è sulle manifestazioni
assiali
Dougados et al, Arthritis Rheum 1995
Clegg et al, Arthritis Rheum 1999
„
non è in grado di rallentare/bloccare la
progressione radiologica
Rahman et al, J Rheumatol 1998
TERAPIA CON CsA NELLA AP
„
„
„
nel 1980 sono comparse descrizioni di casi
di psoriasi trattati con CsA in cui vi era
miglioramento della artrite associata
successivamente sono comparsi numerosi
studi aperti che hanno evidenziato
l’efficacia della CsA nella AP
in uno studio controllato su 35 pts con AP
la CsA e il MTX era ugualmente efficaci
Spadaro et al, Clin Exp Rheumatol 1995
Salvarani et al, Clin Exp Rheumatol 2002
TERAPIA CON CsA NELLA AP
„
su 170 pts trattati con CsA in 16 studi solo
il 6% sospendeva il farmaco per
nefrotossicità
Olivieri et al, Semin Arthritis Rheum 1997
TERAPIA CON CsA NELLA AP
„
„
„
„
„
è efficace nella artrite periferica
è più efficace della SSZ
non vi sono dati sulla sua efficacia nella
malattia assiale
non vi sono dati sulla sua efficacia sulla
progressione del danno radiologico
è un terapia sicura
Salvarani et al, Clin Exp Rheumatol 2002
Salvarani et al, J Rheumatol 2001
Artrite psoriasica: terapia con MTX
1.
2.
3.
Black RL, et al. Methotrexate therapy in psoriatic arthritis. Doubleblind study on 21 patients. JAMA 1964. 21 p., MTX 1-3 mg/Kg
ogni 10 gg. (3 iniezioni): riduzione significativa del n° di
art. dolenti e tumefatte, miglioramento range art.
movimento e riduzione della VES. Pancitopenia 7 p
Willkens RF, et al. Randomized, double-blind, placebo controlled trial
of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum
1984. 37 p.; studio prospettico di 12 settimane; MTX 7,5-15
mg/sett.. Nessuna differenza significativa per: n° di art.
dolenti e tumefatte, rigidità mattutina, psoriasi. VMAM
(medico): miglioramento significativo (p=0,001). Nessun
evento avverso severo
Abu-Shakra M, et al. Longterm methotrexate therapy in psoriatic
arthritis: clinical and radiological outcome. J Rheumatol 1995. studio
retrospettivo, caso-controllo, durata 24 mesi: 23/38 p.;
simile efficacia su risposta clinica e danno radiologico
TERAPIA CON MTX NELLA AP
„
„
„
è efficace nella artrite periferica
non è più efficace delle altre terapie di
fondo (?)
non vi sono dati sulla sua efficacia
nella malattia assiale
Salvarani et al, Clin Exp Rheumatol 2002
TERAPIA CON MTX NELLA AP
„
„
„
„
non è probabilmente efficace sulla
progressione del danno radiologico (?)
è un terapia sicura
non vi sono dati sufficienti per valutarne
l’efficacia
è in corso uno studio controllato,
multicentrico inglese
Salvarani et al, Clin Exp Rheumatol 2002
Leflunomide nell’Artrite
nell’Artrite Psoriasica
I risultati di un RCT evidenziano che leflunomide:
è efficace sull’artrite periferica, e sulle lesioni cutanee
è ben tollerata
migliora la qualità della vita
non vi sono dati sulla sua efficacia nella malattia
assiale e sulla progressione del danno radiologico
Kaltwasser J. P. et al. Arthritis & Rheumatism 2004.
Recommendations of the Italian Society of
Rheumatology for the use of biologic
(TNF-α blocking) agents in the treatment
of psoriatic arthritis
C Salvarani, I Olivieri, N Pipitone,
F Cantini, A Marchesoni, L Punzi,
R Scarpa, M Matucci-Cerinic
Clin Exp Rheumatol 2006
PsA with peripheral arthritis
Anti-TNF-α therapy should be considered if:
„
They have not responded to full therapeutic or tolerated
doses (unless contraindicated) of at least 2 NSAIDs over 3
months, to at least two steroid injections (in cases of monoor oligoarthritis) as well as to at least two of the DMARDs
most commonly used in PsA (methotrexate, ciclosporin,
sulfasalazine, leflunomide), administered alone or in
combination for at least three months (we consider “full
therapeutic doses” 2-3 grams per day for sulfasalazine, 20 mg
per week for methotrexate, 3-5 mg per kg/body weight per
day for ciclosporin, and 20 mg per day for leflunomide)
The Challenge of Early Diagnosis of PsA
„
As in RA, the use of anti-TNFα agents only after
failure of traditional DMARDs in PsA will probably
change in the near future, since early intervention
should be the most effective clinical strategy in PsA
Olivieri I et al, J Rheumatol 2008
Effects of TNF-α blockade on metabolic syndrome components
in PsO and PsA and additional lessons learned from RA
Channual et al, Dermatologic Therapy 2009
„
„
„
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MetS is a cluster of several interrelated cardiometabolic
risk factors: central obesity, atherogenic dyslipidemia,
hypertension, and impaired glucose tolerance
PsO and PsA patients are highly predisposed to MetS,
diabetes and cardiovascular disease
TNF-blockers improve insuline resistance and
sensitivity in PsO and PsA
The effects of TNF-blockers on blood lipids in PsO
and PsA patients are presently unclear
Effects of TNF-α blockade on metabolic syndrome components
in PsO and PsA and additional lessons learned from RA
Channual et al, Dermatologic Therapy 2009
„
„
Long term study show statistically significant
weight gain and an increase in BMI after TNFblockade in PsO and PsA patients
TNF-blockers may improve cardiometabolic risk in
PsO and PsA patients reducing systemic
inflammation (reduction in IL-6, TNF-α and CRP)
and improving endothelial function
Effects of etanercept in patients with
the metabolic syndrome
Bernestein et al, Arch Intern Med 2006
„ Study: RCTs on patients with MetS alone
treated with etanercept for 4 weeks
„ Results: Significant decrease in IL-6, >2
mg/L reduction in CRP, increase in
adinopectin (an insulin sensitizer)