LA TERAPIA DELLA MALATTIA DI BEHÇET CON FARMACI BIOTECNOLOGICI

1. LA TERAPIA DELLA
MALATTIA DI BEHÇET CON
FARMACI BIOTECNOLOGICI
C. Salvarani and N. Pipitone
Unità Operativa di Reumatologia
Ospedale di Reggio Emilia

2. La Terapia della Malattia di Behçet
EULAR recommendations for the management of BD
Anti-
Anti-TNF therapy in the management of BD: review
and basis for recommendations
Infliximab for the treatment of Neuro-Behçet
Neuro-
Infliximab in the treatment of Budd-Chiari syndrome
Budd-
in patients with BD
Interferon-
Interferon-alpha2a in the treatment of BD uveitis

3. EULAR Recommendations for
the management of Behçet’s disease
Ann Rheum Dis, 2008; 67:1656-1662
67:1656-
Management of Behçet’s disease: a systematic literature
review for the EULAR evidence based Recom-
Recom-
mendations for the management of Behçet’s disease
Ann Rheum Dis published online 17 Apr 2008
G Hatemi, D Bang, B Bodaghi, AM Chamberlain, A Gul, MH Houman, I
Kötter, I Olivieri, C Salvarani, PP Sfikakis, A Silman, A Siva,
MR Stanford, N Stübiger, S Yurdakul, H Yazici

4. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
Objectives: to develop EULAR recommendations for the
management of Behçet’s Disease (BD), in an evidence and
expert opinion based approach
Methods:
- the multidisciplinary expert committee consisted of 9
rheumatologists, 3 ophthalmologists, 1 internist, 1
dermatologist and 1 neurologist, representing 6 European
countries, Tunisia and Korea
- Systematic literature search was performed using MedLine
and Cochrane library through December 2006
- Strength of each recommendation was determined
according to the level of evidence and the experts opinions

5. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
1. Any patient with BD and inflammatory eye disease
affecting the posterior segment should be on a
treatment regime, which includes azathioprine and
systemic corticosteroids
2. If the patient has severe eye disease defined as >2 lines
of drop in visual acuity on a 10/10 scale and/or retinal
disease (retinal vasculitis or macular involvement) it is
recommended that either cyclosporine A or infliximab
be used in combination with azathioprine and
corticosteroids; alternatively interferon-alpha with or
interferon-
without corticosteroids could be used

6. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
3. There is no firm evidence to guide in the managing
major vessel disease in BD. For the management of
acute deep vein thrombosis immunosuppressive agents
like corticosteroids, azathioprine, cyclophosphamide or
cyclosporine are recommended. For the management of
both pulmonary and peripheral arterial aneurysms,
cyclophosphamide and corticosteroids are
recommended
4. There are no controlled data on, or evidence of benefit
from uncontrolled experience with: anticoagulants,
anti-
anti-platelet or fibrinolytic agents in the management of
deep vein thrombosis or for the use of anticoagulation
for the arterial lesions

7. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
5. There is no evidence based treatment that can be
recommended for the management of
gastrointestinal involvement of BD. Agents such as
sulfasalazine, corticosteroids, azathioprine, TNF
antagonists or thalidomide should be tried first
before surgery, except in emergencies
6. In most patients with BD, arthritis can be managed
with colchicine

8. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
7. There are no controlled data to guide the
management of CNS involvement in BD. For
parenchymal involvement agents to be tried may
include corticosteroids, interferon-alpha,
azathioprine, cyclophosphamide, methotrexate and
TNF antagonists. For dural sinus thrombosis
corticosteroids are recommended
8. Cyclosporine should not be used in BD patients with
CNS involvement unless necessary for intraocular
inflammation

9. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
9. The decision to treat skin and mucosa involvement will
depend on the perceived severity by the physician and the
patient. Mucocutaneous involvement should be treated
according to the dominant or co-dominant lesions present
• Topical measures (i.e. local steroids) should be the first line
of treatment for isolated oral and genital ulcers
• Acne-like lesions are usually of cosmetic concern only.
Thus, topical measures as used in acne vulgaris are
sufficient

10. EULAR RECOMMENDATIONS FOR THE
MANAGEMENT OF BEHÇET’S DISEASE
Colchicine should be preferred when the dominant
lesion is genital ulcer or erythema nodosum
Leg ulcers in BD might have different causes.
Treatment should be planned accordingly
Azathioprine, interferon-alpha and TNF antagonists
may be considered in resistant cases

11. Anti-
Anti-TNF therapy in the management of BD –
review and basis for recommendations
Rheumatology, 2007
PP Sfikakis, N Markomichelakis, E Alpsoy, S
Assaad-
Assaad-Khalil, B Bodaghi, A Gul, S Ohno,
N Pipitone, M Schirmer, M Stanford, B Wechsler, C
Zouboulis, P Kaklamanis, H Yazici

12. Posterior segment intraocular inflammation
In unilateral involvement with visual acuity < 0.2
IFX can be considered; in bilateral involvement IFX
can be used as first line treatment
In patients with 2 or more relapses/year despite, or
intolerant to, adequate doses of AZA and/or Cs, or
interferon α-2a, combined with prednisolone (<7.5
mg/day), IFX can be used

13. Parenchymal CNS involvement
In patients refractory to treatment with pulse
cyclophosphamide and prednisolone
(1 mg/Kg/day), or in those who relapse while
on maintenance with AZA and prednisolone
(< 7.5 mg/day) IFX may be tried

14. Intestinal inflammation
In patients who have failed two
immunosuppressive agents (AZA, Cs,
MTX, thalidomide, interferon α-2a) and
require prednisolone at a dosage > 7.5
mg/day, IFX may be used

15. Mucocutaneous manifestations
In patients with poor quality of life
despite, or intolerant to, adequate doses
of AZA, colchicine or thalidomide and
require prednisolone at a dosage > 7.5
mg/day, etanercept or IFX may be used

16. Arthritis
In patients who have failed two
immunosuppressive agents including
MTX and require prednisolone at a
dosage > 7.5 mg/day, etanercept or IFX
may be used

17. Infliximab for the Treatment of Neuro-Behçet’s
Neuro-
disease: a case series and review of the literature
Arthritis Rheum, 2008
N Pipitone, I Olivieri, A Padula, S D’Angelo,
A Nigro, G Zuccoli, L Boiardi, C Salvarani

18. Neuro-Behçet syndrome
Akmar-Demir et al, Neuroradiology 2003
The reported frequency ranges from 2.2% to 49%
with 2 major types:
1) Parenchymal involvement (meningo-encephlitis):
(meningo-
- the lesions are usually in the brain-stem, basal
brain-
ganglia or deep hemisphere white matter
- tendency to resolve over time
2) Dural sinus occlusion

19. Infliximab for the Treatment of Neuro-Behçet’s
Neuro-
disease: a case series and review of the literature
Objective: To evaluate the efficacy of infliximab in a
series of patients with NB
Methods:
- We reviewed all patients with a diagnosis of BD followed
at two Italian rheumatological centers
- We report 8 cases of NB treated with TNF-α blockers
TNF-
- Furthermore, the published papers on the use of anti-
anti-
TNF-
TNF-α therapy for NB were reviewed

20. Results:
Including the 4 published cases, IFX was prescribed
for new-onset NB in 8 patients and for relapsing NB
new-
in 4 others
Adjunct therapy given together with IFX included
glucocorticoids, methotrexate, cyclophosphamide,
ciclosporin, and colchicine
In all cases, IFX was used at a dose of 5 mg/kg
except for two cases in which the dose was 3 mg/kg

21. Results:
All patients had a satisfactory clinical response,
while brain MRI showed partial regression of
parenchymal lesions in all 10 patients in whom it
was performed before and after IFX therapy
At follow-up, virtually all patients were in clinical
follow-
remission
No side-effects were noted
side-

23. Infliximab for the Treatment of Neuro-Behçet’s
Neuro-
disease: a case series and review of the literature
Conclusion:
Taken together, these data suggest that
infliximab may be effective and safe to treat
Neuro-
Neuro-Behçet’s disease

24. Sindrome di Budd-Chiari nella Malattia di Behçet
Bayraktar et al, Am J Gastroenterol 1997
14/493 (2,8%) pazienti avevano trombosi delle vene
sovraepatiche
10/14 pazienti associavano trombosi totale della vena
cava inferiore e rappresentava il subset a prognosi
peggiore (sopravvivenza media: 10,3 mesi)
il 26% dei casi di sindrome di Budd-Chiari
Budd-
associavano malattia di Behçet

25. Infliximab in the treatment of hepatic vein thrombosis
(Budd-Chiari syndrome) in 3 patients with BD
Seyahi E et al, Rheumatology 2007
Two patients died, but they had almost end-stage
end-
liver failure when IFX was given
In the third patients, although there was a regression
in the size of the thrombus in the inferior vena cava,
IFX was stopped for the simultaneous development
of cranial sinus thrombosis
The experience of 3 patients with BD and Budd-
Budd-
Chiari syndrome was not promising

26. INTERFERON α-2a

27. Rationale for using IFN alfa in BD
The mechanism of action remains to be
elucidated
Viral and bacterial infections, mainly
herpes simplex and certain strains of
streptococci, have been proposed as
etiologic agents
Lehner et al, 1995

28. Rationale for using IFN alfa in BD
It improves the elimination of foreign antigens:
- enhancement of HLA class I antigen expression on
lymphoid cells
- enhancement of T and NK cell cytoxicity
- it diverts the T cell response in the direction of Th1
It inhibits the proliferation of γδ T cells
It inhibits the adhesion of T cells to endothelial
cells
Belardelli et al, Immunol Today 1996; Hasan et al, Lancet 1996

29. Interferon alfa for the uveitis of BD
Authors IFN Combined Design Patient
type therapy number
Hamurydan et al, α 2b Aza open 10
IMAJ 2002
Randomized,
Alpsoy et al, α 2a - 44
placebo-
placebo-controlled,
Arch Dermatol 2002 double blind
Retrospective,
Çalgüneri et al,
algü - 29
α
Open
Ann Rheum Dis 2003
Prospective,
Kötter et al, α 2a - 50
Open
Br J Ophthalmol 2003
Retrospective,
Tugal-Ttkun et al,
Tugal- al, α 2a - 44
Open
Graefe’s Arch Clin
Exp Ophthalmol 2006

30. Interferon alfa for the uveitis of BD
Authors Criteria Therapy Ocular
duration disease
for BD
Hamurydan et al, 10 (100%)
ISG 24 weeks
IMAJ 2002
Alpsoy et al, 9/44 (20%)
ISG 3 months
Arch Dermatol 2002
Çalgüneri et al,
algü Mean: 17/29 (59%)
ISG
Ann Rheum Dis 2003 22 months
Kötter et al, 50 (100%)
ISG 24, 52 weeks
Br J Ophthalmol 2003
Tugal-
Tugal-Ttkun et al,
al, Mean: 44 (100%)
ISG
Graefe’s Arch Clin Exp 12 months
Ophthalmol 2006

31. Kötter et al, The use of interferon alfa in BD:
review of the literature
Semin Arthritis Rheum 2004
32 reports and 4 abstracts were included in the
analysis (reports published until July 2002)
IFNα
IFNα was administered to 338 pts: IFNα-2a: 264 pts,
IFNα
IFNα
IFNα-2b: 74 pts
Higher IFNα doses were more effective than low doses
IFNα
and led to up to 56% long-term remissions after IFNα
long- IFNα
discontinuation:
median dosage in studies with relapses: 3.000.000 iU per week
-
median dosage in studies with long term remission: 24.000.000
-
iU per week

32. Comparison of IFNα-2a and IFNα-2b
Kötter et al, The use of interferon alfa in BD:
review of the literature, Semin Arthritis Rheum 2004
Complete remissions were more common with
IFNα
IFNα-2a than with IFNα-2b:
IFNα
- 91% vs 6% for ocular manifestations
- 53% vs 6% for mucocutaneous
manifestations
- 74% vs 32% for articular symptoms

33. Comparison of IFNα-2a and IFNα-2b
Kötter et al, The use of interferon alfa in BD:
review of the literature, Semin Arthritis Rheum 2004
However complete + partial remissions were
similar:
similar:
- 94% vs 100% for ocular manifestations
- 93% vs 61% for mucocutaneous
manifestations
- 95% vs 100% for articular symptoms

34. Adverse effects
The use of interferon alfa in BD:
review of the literature, Semin Arthritis Rheum 2004
Flu-like syndrome: 88%
Flu-
Mild leukopenia: 30%
Alopecia: 10%
IFNα
IFNα discontinuation: 2 pts for alopecia, 2 pts for
diarrhea, 2 pts for leukopenia

35. Recommended INF-α regimen
The use of interferon alfa in BD:
review of the literature, Semin Arthritis Rheum 2004
to start with a higher dosage: 6 or even
9,000,000 iU per day
reduce it to 4,500,000 iU per day after 4 weeks,
and to 3,000,000 iU per day after another 4
weeks
then reduce to the maintenance dosage of
3,000,000 iU 3 per week after remission is
achieved
continue it for at least 8 weeks after remission

36. Long-term efficacy and safety of low-dose interferon
alpha2a in severe uveitis associated with BD
Gueudry et al, Am J Ophthalmol 2008
A retrospective study showing control of inflammation in
88% of 32 BD patients with uveitis relapsing despite
corticosteroids and immunosuppressive agents treated with
IFN-
IFN-alpha2a 3 million U thrice a week
- mean observation period: 70.6 months (30-129 months)
(30-
- median visual acuity improved from 0.52 to 0.33 (p = 0.005)
2 years after initiation of therapy
- the relapse rate decresed significantly during treatment (from
1.68+
1.68+1.22 relapses/patient/year to 0.11+0.20, p < 0.0001)
0.11+
- IFN-alpha2a was discontinued in 68% of patients after 32 months of
IFN-
treatment (16-50 months)
(16-
- after discontinuation (mean follow-up: 43 months) the relapse rate
follow-
increased from 0.08+0.21 relapses/person/year to 0.74+1.40 (p=0.04)
0.08+ 0.74+

37. Long-term efficacy and safety of low-dose interferon
alpha2a in severe uveitis associated with BD
Gueudry et al, Am J Ophthalmol 2008
Conclusions: IFN-alpha2a is efficient and safe
IFN-
for the long-term management of severe
long-
uveitis associated with BD. It has a potent
corticosteroid-
corticosteroid-sparing effect. Meanwhile it
seems to be a suspensive therapeutic
strategy, even though long-term remission is
long-
possible in some patients

38. Future perspectives
In this era of evidenced-based medicine,
evidenced-
there is an urgent need for controlled,
randomized studies with TNFα and
IFNα
IFNα-2a using standardized outcome
measures
Its efficacy and cost-effectiveness should
cost-
be compared with standard immunosup-
immunosup-
pressants to determine its hierarchy in the
treatment of BD

39. Cost long-term maintenance therapy
with infliximab and IFN-alpha2a
Cost for both drugs in the first year for
a patient of 75 Kg of body weight
Infliximab IFN-
IFN-alpha2a
375 mg per infusion, 5 mg/Kg of 3MU, 3 times a week
body weight every 6 weeks for one year
Real cost for
the hospital 1923.26 X 8.5 = 16,347.71 € 10.27 X 156 = 1602.12 €
3186.6 X 8.5 = 27,086.1 € 25.21 X 156 = 3923.76 €
AIFA cost