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Salvarani carlo nuovi farmaci biologici torino gennaio 2011_14° convegno patologia immune e malattie ra
1. Nuovi Farmaci Biotecnologici nelle
Patologie Reumatiche
e Autoimmuni
C. Salvarani, N Pipitone,
MG Catanoso, L Magnani, F Muratore,
Unità di Reumatologia,
Ospedale di Reggio Emilia
2. Topics
• TNF-blockers and Tocilizumab in Giant
Cell Arteritis and Takayasu Arteritis
• TNF-blockers and Rituximab in ANCA-
associated Vasculitis
• Rituximab in IgG4-related Systemic
Disease
4. Caso Clinico
B.G., Maschio, 63 aa, iperteso, BMI 35.6
Cefalea di nuova insorgenza in sede fronto-temporale dx
e occipitale
Astenia e febbricola serale (37,5 °C – 38 °C )
Tosse stizzosa e secca
Incremento indici di flogosi: VES 120 mm/h, PCR 4,25 mg/dl
5. Caso Clinico: Diagnosi
BIOPSIA A. TEMPORALE DX
DIAGNOSI ISTOLOGICA
Sezioni di vaso arterioso con marcata
flogosi linfomonocitaria transparietale con
cellule giganti
Reperto istologico
diagnostico di
Arterite a Cellule Giganti
Inizia terapia steroidea con Prednisone 50 mg/die
6. Caso Clinico: Follow-up Clinico (2007-2010)
Inizia terapia con prednisone 50 mg/dì
Recidiva di malattia con prednisone < 15 mg/dì
Comparsa di diabete e frattura vertebrale dorsale
Persistenza elevati indici di flogosi (VES: 80-120 mm/h)
Associazione con MTX 15 mg/sett.
Per inefficacia del MTX come risparmiatore di steroide
dopo 1 anno si associa anti-TNFα (prima Infliximab 5 mg/kg,
quindi dopo 12 mesi per inefficacia passa a Etanercept 50 mg/sett)
Aprile 2010: CT-PET positiva e VES 110 mm/ora
7. CT-PET Whole Body April 2010
patologico accumulo del FDG a livello delle carotidi interne (prevalente a sx),
dell’arco dell’aorta e dell’aorta ascendente espressione
di persistente flogosi vascolare in dette sedi
8. Caso clinico: inizio Tocilizumab 8 mg/Kg
ogni 4 sett.
Giugno Luglio Agosto Settembre Ottobre
VES
mm/1h 120 25 18 20 8
PCR
(mg/dl) 4,70 0,28 0,16 0,36 0,30
Prednisone
(mg/dì) 12,5 12,5 12,5 10 7,5
Segni/Sintomi
Costituzionali SI NO NO NO NO
9. Glucocorticoids are
the treatment of choice for GCA
• Adequate GC doses quickly suppress clinical
manifestations of GCA and prevent ischemic
complications
• If visual loss has occurred before starting
therapy, it is usually not reversed
• An empiric initial dose of 40-60 mg daily of
prednisone (or equivalent) as a single or
divided dose is recommended
Salvarani et al, Lancet 2008
10. Glucocorticoids are
the treatment of choice for GCA
• The needed duration of GC therapy is variable,
but in most patients it can be discontinued within
1-2 years
• Some patients have a chronic relapsing course
and may require low doses of GCs for several
years or even indefinitely
Salvarani et al, Lancet 2008
11. Points to consider in the therapy of GCA
• vision loss or cerebrovascular accidents occur in
a minority of patients and are very unusual once
GC therapy has been initiated
• The potentially catastrophic thoracic aneurysm
and dissection occur only in 7.6% and 1% of
patients, years after the onset of the disease
Salvarani et al, Lancet 2008 and Arthritis Rheum 2005
12. Points to consider in the therapy of GCA
• The morbidity of GCA is related to the
impact of long-term therapy with
glucocorticoids in elderly patients, who
often have many comorbidities
13. Gucocorticoid-related side-effects in GCA
• In a population based study: adverse events
associated with GCs were recorded in 103
(86%) of 120 patients and 2 or more events
occurred in 70 patients (58%)
• Age and higher cumulative dose of GCs were
associated with the development of adverse
GC side effects
Proven et al, Arthritis Rheum 2003
14. Major adverse events that occurred in 103 of 120
patients with giant cell arteritis
Type of adverse event Patients with the event, number (%)
Diabetes mellitus 11 (9)
Total fractures 46 (38)
Hip fracture 19 (16)
Vertebral fracture 27 (23)
Colles' fracture 3 (2.5)
Other fractures 11 (9)
Gastrointestinal bleeding 5 (4)
Hypertension 26 (22)
Infection 37 (31)
Posterior subcapsular 49 (41)
cataract
15. Therapy of GCA
We need effective treatments in
GCA to reduce the exposure
to glucocorticoids
16. Steroid-sparing agents in GCA:
evidence from RCTs
• Methotrexate: 3 RCTs with different results
and 1 meta-analysis
• Azathioprine: 1 RCT
• Infliximab: 1 RCT
• Etanercept: 1 RCT
• Alternate day GC treatment: 1 RCT
• Pulse GC therapy: 2 RCTs
17. What is the evidence from randomized
controlled trials (RCTs)?
• MTX may have a small steroid-sparing effect
• MTX is effective only after a latency period of
24-36 weeks
• High MTX dosages (20-25 mg/week) have not
been adequately studied
• MTX does not decrease the incidence of
steroid-related side effects
• Azathioprine may have a small steroid-sparing
effect and it may be tried if MTX is contro-
indicated or not tolerated
18. What is the evidence from randomized
controlled trials (RCTs)?
• Infliximab does not have a steroid-sparing
effect in newly diagnosed patients
• Etanercept could have a steroid-sparing effect
in patients with relapsing disease
• Infliximab and etanercept do not reduce the
incidence of steroid-related side effects in the
short-term
• A GC-sparing effect for infliximab may not be
completely excluded: the study was too small
to definitively identify small benefits
19. What is the evidence from randomized
controlled trials (RCTs)?
• Before completely excluding a potential
therapeutic role for TNF-blockers, a large RCT
should be performed enrolling only GCA
patients with relapsing disease
• Alternate-day GC regimen is not
recommended
• Additional investigations are needed on the
use of pulse GC at the onset of treatment for
GCA to confirm whether this regimen reduces
GC toxicity
20. Future directions in GCA therapy
Salvarani et al, Lancet 2008
• RCTs are needed to assess new
therapeutic agents
• Strong evidence suggest that IL-6
has a major role in sustaining
disease activity in GCA
21. IL-6 and Disease Activity in GCA
• IL-6 concentrations, but not TNF alpha, are
increased in GCA patients
• GCs rapidly suppress IL-6 production
• There is a close correlation of plasma IL-6
concentrations with clinical symptoms
• Vasculitic lesions in GCA samples are
characterized by in situ production of IL-6, IL-1
beta, and TGF-beta1 mRNA, indicative of
macrophage activation
Roche et al, Arthritis Rheum 1993;
Weyand et al, Ann Intern Med 1994
22. IL-6 and Disease Activity in GCA
• Plasma IL-6 is more sensitive than
ESR for indicating disease activity
• Circulating IL-6 may persist
elevated in GCA patients after long-
term followup and remain higher in
patients with more relapsing
disease
Weyand et al, Arthritis Rheum 2000
Garcia-Martinez et al, Arthritis Rheum 2010
23. Points to consider in the therapy
of Takayasu Arteritis
• 20% of patients have a self-limited, monophasic
inflammatory episode
• 80% have a progressive or relapsing/remitting course
• Serial angiographic studies show that new lesions can
be found in 61% of patients, even when the arteritis is
thought to be in remission
• Fixed vascular lesions are not reversed by drug therapy
• GCs constitute the first line of treatment, with
suggested initial dosages of 0.5 to 1 mg/Kg/day
Kerr et al, Ann Intern Med 1994;
Liang and Hoffman, Current Opin Rheumatol 2004
24. Limitations of therapy and a guarded prognosis
in an American cohort of TA patients
Maksimowicz-McKinnon et al, Arthritis Rheum 2007
• Results:
93% of patients attained disease remission of
any duration, but only 28% had sustained
remission of at least 6 months' duration after
prednisone was tapered to <10 mg daily
• Conclusion:
although improvement of symptoms in TA
usually follows GC therapy, relapses and
anatomic progression usually occur with
dosage reduction
25. Role of Immunosuppressive Agents in TA
They are addded to GCs:
• Halting disease progression
• Reducing GC-related morbidity
26. Traditional immunosuppressive agents
• Only open-label pilot studies in GC-resistant cases:
- methotrexate
- micophenolate mofetil
- azathioprine
- oral cyclophosphamide
Hoffman et al, Arthritis Rheum 1994; Daina et al, Ann Intern Med 1999;
Shinjo et al, Clin Rheumatol 2007; Valsakumar et al, J Rheumatol 2003;
Shelhamer et al, Ann Intern Med 1985; Hoffman et al, Arthritis Rheum 2004;
Molloy et al, Ann Rheum Dis 2008
27. Anti-TNF therapy in patients with
refractory TA: long-term follow-up
Molloy et al, Ann Rheum Dis 2008
• Methods: Retrospective single-centre study of 25
patients with refractory TA treated with infliximab
(21) or etanercept (9) for up to 7 years
• Results: Following anti-TNF therapy remission was
achieved and prednisone was discontinued in 15
patients (60%) and successfully tapered below 10
mg/day in an additional 7 patients (28%)
• Conclusions: anti-TNF therapy may lead to durable
remission and reduction in glucocorticoid
requirements in most patients with refractory TA
28. IL-6R inhibition in refractory TA
• IL-6R inhibition with tocilizumab improved the
clinical manifestations and the abnormal
laboratory findings in one patient who needed a
daily prednisone dosage of 30 mg/day and was
refractory to several immunosuppressive
agents
Nishimoto et al, Arthritis Rheum 2008
29. IL-6 and Disease Activity in TA
• IL-6 is strongly expressed in aortic tissue
of TA patients
• IL-6 is probably locally produced at the
site of aortic inflammation
• All patients with active disease have
elevated serum IL-6 levels
Seko et al, Circulation 1996
Noris et al, Circulation 1999
Salvarani et al, Clin Exp Rheumatol 2003
Park et al, Rheumatology 2006
30. IL-6 and Disease Activity in TA
• Clinical improvement was associated with
a marked reduction in serum IL-6 levels
• A positive correlation was found between
IL-6 levels and the disease activity score
(NIH criteria for disease activity)
Noris et al, Circulation 1999
Salvarani et al, Clin Exp Rheumatol 2003
Park et al, Rheumatology 2006
31. Take-Home Messages
• TNF-blockers as steroid-sparing agents
TNF- steroid-
are not effective in GCA
• TNF-blockers are effective in refractory
TNF-
Takayasu arteritis
• IL-6 inhibition with tocilizumab might be a
IL-
logical target for future RCTs in GCA and
Takayasu arteritis
33. Wegener’s granulomatosis:
Early Outcomes
• Natural History:
- Mean survival time: 5 months
- Mortality: 82% in 1 year
• Glucocorticoid-treated generalized WG
- Mean survival time: 12.5 months
Fauci S and Wolff SM, Medicine 1973
34. The Fauci-Wolff Protocol:
NIH Longitudinal Series (began 1968)
• Cyclophosphamide (CYC) 2 mg/Kg/day
• Glucocorticoids:
- Pulse methylprednisolone (1g/day X 3)
- Prednisone 1 mg/Kg/day
- Tapered to qod after 3 months
• Typical duration of therapy:
- Glucocorticoids: 12 months
- CYC: Remission + 12 months
Hoffman GS et al, Ann Intern Med 1992
35. CYC Therapy for AAV
The Good/The Bad
• 91% marked • 42% permanent morbidity
improvement - 46% serious infections
- 43% hemorrhagic cystitis
- 33-fold risk of bladder CA
• 75% complete - 11-fold risk of lymphoma
remission - 57% infertility
Steroid-induced damage:
Cushingoid features, weight gain,
hypertension, cataracts, fractures
Hoffman et al, Ann Intern Med 1992
37. Take-Home Points from RCTs
• A short course of CYC for remission induction,
followed by a longer course of methotrexate or
azathioprine is an effective treatment strategy
for AAV
• The pulse CYC (15 mg/kg pulse q2wkX3, then
q3wk) induces remission as well as the daily
oral regimen at a reduced cumulative CYC dose
and causes fewer cases of leukopenia
Jayne D et al, N Engl J Med 2003 (CYCAZAREM);
Pagnoux C et al, N Engl J Med 2008 (WEGENT);
de Groot K et al, Ann Intern Med 2009 (CYCLOPS);
39. Wegener’s Granulomatosis
Etanercept Trial (WGET)
• Etanercept in addition to standard therapy is not
effective for the maintenance of remission in pts
with WG
- No difference in time to remission
- No difference in frequency of remission
- No difference in duration of remission
- No difference in severity or frequency of flares
- Increased risk of cancer in patients treated with
etanercept (6 vs 0, P = 0.01)
WGET Research Group, N Engl J Med 2005
41. RTX versus CYC in ANCA-Associated Renal Vasculitis
(RITUXVAS) Jone RB et al, N Engl J Med 2010
• Randomized (3:1), controlled, open-label
• 44 patients
• All ANCA-positive, all new diagnosis
• All had severe renal disease
• Comparing:
RTX plus 2 infusions of CYC (n=33)
Intravenous CYC for 6 months, followed by oral AZA
(n=11)
• Everybody remained on ~ 10 mg/day of prednisone
• Primary endpoints: sustained remission at 12 months
and severe adverse events
42. Main RITUXVAS Results
No difference between treatment arms of:
• Mortality: 18% in each arm
• Sustained remission at 12 months:
- RTX 76% vs CYC 82%
• Time to remission: RTX 90 days vs CYC 94 days
• Relapse rate
• Time to relapse
• Improvement of renal function
• Adverse events rate
Conclusion: over 12 months one course of RTX
achieves the same results as 6 months of CYC
followed by AZA
Jone RB et al, N Engl J Med 2010
43. RTX versus CYC for ANCA-Associted Vasculitis (RAVE)
Stone JH et al, N Engl J Med 2010
• Randomized (1:1), double blind
• 197 patients (newly diagnosed or relapsing disease)
• All ANCA-positive
• Limited disease (not requiring CYC) and too severe disease
(mechanical ventilation because of alveolar hemorrhage or serum
creatinine > 4 mg/dL) were excluded
• Comparing:
RTX plus daily placebo-CYC (n=99), then placebo-AZA for pts in
remission between 3-6 months
Daily CYC (2 mg/Kg) plus placebo-RTX infusions (n= 98), then daily
AZA (2 mg/Kg) for pts in remission between 3-6 months
• Primary endpoint: remission without the use of prednisone at 6
month
44. Main RAVE Results
No difference between treatment arms of:
• Remission without the use of prednisone at 6 months:
- RTX 64% vs CYC 53%
- RTX 67% vs CYC 42% (p=0.01) for relapsing disease
• Improvement of renal function
• Adverse events rate
• Loss of proteinase 3-ANCA production occurred more frequently
with RTX than with CYC
Conclusion: RTX was not inferior to daily CYC
for induction of remission and may be superior in
relapsing disease
Stone JH et al, N Engl J Med 2010
45. Rituximab Dosage
• RITUXIVAS and RAVE trials used rituximab at a dose
of 375 mg per square meter per week for 4
consecutive weeks
• However, in a retrospective evaluation of 65 sequential
patients receiving RTX for refractory AAV there was no
difference in efficacy between 4 infusions of 375
mg/m2 each given 1 week apart or 2 infusions of 1 gm
each given 2 weeks apart
Jones RB et al, Arthritis Rheum 2009
46. Take-Home Messages
• Available data do no support the use of anti-TNF therapy
in AVV
• Results from 2 RCTs comparing RTX to CYC complement
each other:
- RTX is effective as CYC for newly diagnosed pts with
severe AAV
- RTX seems to be superior for pts with severe relapses
- RTX is preferable for young patients who want to
preserve their fertility
• More data on RTX for maintaining remission in AAV are
needed
52. Rituximab therapy leads to rapid decline of serum IgG4
levels and prompt clinical improvement in IgG4-RSD
Khosroshahi et al, Arthritis Rheum 2010
• Glucocorticoids have become a standard
therapy for AIP
• AIP relapses in one third of patients treated with
glucocorticoids
• Experience with traditional DMARDs as steroid
sparing agents is limited
• Treatment with rituximab led to prompt clinical
and serological improvement in 4 patients with
refractory IgG4-RSD
53. Take-home message
• Rituximab is a viable treatment option
for patients with IgG4-RSD that is
refractory to conventional
immunosuppressive therapy
54. Ringraziamenti
Reumatologia
Dr GL Bajocchi, Dr PL Macchioni, Dr N Pipitone,
Dr.ssa F Rossi, Dr G Germanò, Dr.ssa L Dardani,
Dr.ssa MG Catanoso, Dr A Caruso,
Dr.ssa I Chiarolanza, Dr.ssa G Restuccia,
Dr.ssa A Ghinoi, Dr L Magnani, Dr F Muratore
Anatomia Patologica
Dr A Cavazza
Oculistica
Dr L Cimino
Medicina Nucleare
Dr A Versari
Radiologia
Dr G Zuccoli, Dr A Levrini
