2009 Convegno Malattie Rare Buzio [23 01]
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Transcript of 2009 Convegno Malattie Rare Buzio [23 01]
The Treatment of Idiopathic Retroperitoneal Fibrosis
Augusto Vaglio, MD
Carlo Buzio, MDDept. of Clinical Medicine, Nephrology and
Health Science, University of Parma
Retroperitoneal fibrosis: idiopathic and secondary forms
Idiopathic (75%) Secondary (25%)
• Drugs (eg, ergotamine, methyldopa)
• Malignancies (eg, lymphoma, sarcoma, carcinoma of the GI tract, breast, prostate)
• Infections (eg, TB, actinomycosis)
• “pure” idiopathic form
• Associated with systemic autoimmune diseases (SLE, rheumatoid arthritis)
• Infections (eg, TB, actinomycosis)
• Radiotherapy
• Surgery (eg, colectomy, hysterectomy lymphadenectomy)
• Other (eg, Erdheim-Chester disease, amyloidosis, trauma)
Vaglio A, Palmisano A, Corradi D, et al. Rheum Dis Clin North Am 2007
Idiopathic retroperitoneal fibrosis: clinical manif estations
Clinical manifestations at disease onset
Baker et al. (60 patients)
Kardar et al.(12 patients)
Our series (92 patients)
Pain (e.g. abdominal, back) 68% 91% 87%
Constitutional symptoms 60% 50% 70%
Varicocele/hydrocele/testicular pain n.a. 8% 46%
Constipation n.a. n.a. 20%
Polyuria and/or frequency 26% n.a. 13%
Claudication n.a. n.a. 11%
Leg edema n.a. 17% 11%
Deep vein thrombosis n.a. n.a. 8%
Oliguria 10% 8% 3%
Dysuria n.a. 40% 6%
Ureteral involvement
Overall 100% 100% 79%
Unilateral 18% 42% 57%
Bilateral 82% 58% 43%
Baker LR et al. Br J Urol 1987; Kardar AH, et al. J Urol 2002
Treatment of idiopathic retroperitoneal fibrosis: m ain aims
• Relieve obstructive complications (mainly ureteral)
• Switch off the systemic inflammatory response
• Induce regression of the retroperitoneal mass
• Induce sustained remission/prevent relapses
Relief of ureteral obstruction- I
Ureteral obstruction occurs in 70-100% of IRF patients; unilateral atpresentation in 20-60% of the cases, it often shows contralateralprogression within days to months.
Bilateral ureteral involvement is the major cause of acute renal failure inIRF patients (about 50% of the cases).
Traditional approach: surgical ureterolysis
Ureterolysis (± intraperitoneal transposition) + omental wrapping
Allows multiple biopsies to be performed
Does not prevent progression/relapses
50% relapse if treated with surgery alone vs 10-30% with surgery+medical therapies
Laparoscopy vs Open
Shorter hospital stay and lower transfusion rates
Conversion rate to open approx 20%Srinivasan AK, et al. J Urol 2008courtesy of Dr. S. Ferretti, Urology, Parma
Relief of ureteral obstruction- II
“Conservative” approach
Ureteral double-J stents (cystoscopically placed) or nephrotsomy tubes + medical therapy
Generally well tolerated and safe
Complications: infections, pain, hematuria
Higher relapse rates (25%-72%) in comparison with surgery+ steroids
van Bommel EF, et al. Am J Kidney Dis 2007; Fry AC, et al. Nephron Clin Pract 2008
“Conservative” Surgery + medical therapy
Non-invasive
Minor complications
No biopsy
High relapse rates
Invasive
Post-operative complications
Multiple biopsies
Low relapse rates
Vaglio A, Buzio C. UpToDate
Medical therapy: glucocorticoids
Suppress the retroperitoneal inflammation and the systemicacute-phase response
May inhibit fibroblast proliferation and collagen deposition
Act rapidly, inducing a prompt remission of symptoms and acute-phase reactants
May also induce rapid resolution of obstruction
van Bommel EF, et al. Am J Kidney Dis 2007van Bommel EF, et al. Am J Kidney Dis 2007
No. pts
Prednisone, initial dose
Treatment duration
Remission rate
Relapse rate
Mean follow-up (months)
Mortality (end of
follow-up)
Higgins et al, 1988 retrospective 13 30-60 mg ≥ 2 yrs 92% 9% 59 NA
Kardar et al, 2002 prospective 10 60 mg 2 yrs 90% 11% 63 0 %
van Bommel et al, 2007 prospective 24 60 mg 1 yr 75% 76% 66 8%
Fry et al, 2008 retrospective 24 30 mg 2-3 yrs 100% 25% 76 25%
Higgins PM, et al. Br J Surg 1988; Kardar AH, et al. J Urol 2002; van Bommel EF, et al. Am J Kidney Dis 2007; Fry AC, et al. Nephron Clin Pract 2008
Medical therapy: other immunosuppressive agents
Azathioprine
Used in three different series (11, 15 and 6 pts) as first-line therapy at a dose of ~ 1.5 mg/kg/day incombination with glucocorticoids; well tolerated but no remarkable advantage over steroids alonein terms of remission and relapse rates.
Harreby M, et al. Scand J Urol Nephrol 1994; Marcolongo R, et al. Am J Med 2004; Moroni G, et al. Nephrol Dial Transplant 2006
Cyclophosphamide
Used in two different series (11 and 10 pts) as first-line therapy at a dose of ~ 2 mg/kg/day orUsed in two different series (11 and 10 pts) as first-line therapy at a dose of ~ 2 mg/kg/day ormonthly iv boluses of 1000 mg, in combination with glucocorticoids; no remarkable advantage oversteroids alone in terms of remission and relapse rates, but severe toxicity (eg, sepsis, death)
Marcolongo R, et al. Am J Med 2004; Warnatz K, et al. Ann Rheum Dis 2005
Mycophenolate mofetil
Used in two different series (7 and 16 pts) as first-line therapy at a dose of ~ 1g bid, in combinationwith glucocorticoids; effective and safe
Scheel PJ, et al. J Urol 2007; Swartz RD et al, Clin Nephrol 2008
Medical therapy: tamoxifen
May act independently of the estrogen receptor-mediated pathway (estrogen receptors are poorlyexpressed by retroperitoneal fibrosis tissue)
Alter the growth factor balance (eventually suppressing fibroblast proliferation?)
Antiangiogenic mechanisms? Immunomodulatory effects?
van Bommel et al. reported that TXF inducedresolution of symptoms in 15 of 19 patients (79%) and(partial or complete) regression of the retroperitonealmass in 12 (63%)
van Bommel EF et al, Ann Intern Med 2006
TXF was always well tolerated, even in the long-term
van Bommel EF et al, Ann Intern Med 2006
Limitations
Low disease severity (ESR, CRP)
Low incidence of obstructive uropathy
Inclusion of RPF secondary to pancreatitis
Vaglio A et al, Ann Intern Med 2006
Medical therapy: main limitations of the available studies
• No randomised controlled trials
• Most studies are retrospective
• The end-points/outcome measures are not adequately reported
• Some studies also include secondary forms of RPF
Randomised trial of prednisone and tamoxifen in idi opathic RPFPatients and Methods- Inclusion/Exclusion criteria
Diagnosis of idiopathic RPF: CT/MRI (retroperitoneal biopsy in patients undergoing surgery or in cases with atypical clinical findings)
Inclusion criteria
• Diagnosis of idiopathic RPF (both non-aneurysmal and aneurysmal forms)
Exclusion criteria
• secondary forms of RPF (e.g. drugs, malignancies, infections, radiotherapy)
• RPF associated with systemic • Age: 18-85 years
• Any technique for ureteral decompression allowed (ureteral stents, nephrostomy tubes, surgical ureterolysis)
• RPF associated with systemic autoimmune or inflammatory diseases
• previous medical treatment for RPF
• hypersensitivity to study drugs
• major systemic infections
Randomised trial of prednisone and tamoxifen in idi opathic RPF
Study design: Prospective, randomised, open-label trial comparing the efficacy of prednisonevs tamoxifen in patients with idiopathic RPF
Primary end-point: rate of disease remission at the end of treatment
Remission: absence of disease-related symptoms, absence of hydronephrosis and normal ESR and CRP
Secondary end-points: rate of disease relapses after the end of treatment
rate of regression of the retroperitoneal mass
major treatment-related and unrelated complications during the follow-up
renal function improvement
Diagnosis of idiopathic RPF
Randomisation
Prednisone 1 mg/kg/day (1 month)
PREDNISONE TAMOXIFEN
Randomised trial of prednisone and tamoxifen in idi opathic RPF
PREDNISONE(0.5 mg/kg/day)
TAMOXIFEN(0.5 mg/kg/day)
CT/MRI (4th month)
Post-treatment follow-up: 16 months
CT/MRI (8th month)
8 monthsprednisone tapering
8 months
40 consecutive idiopathic RPFpatients (2000-2006)
1 patient excluded: revised diagnosis (TB-induced RPF)
39 patients started prednisone 1 mg/kg/day (1 month)
2 patients excluded because of acute steroid
Randomised trial of prednisone and tamoxifen in idi opathic RPF
because of acute steroid toxicity; 1 refused to
continue steroids
36 patients completed one month of prednisone
18 randomised for prednisone
18 randomised for tamoxifen
Prednisone (N=18)
Tamoxifen (N=18)
Gender, M/F 12/6 11/7
Age, median (range)-years 56 (37-84) 60 (38-75)
Non-aneurysmal/aneurysmal RPF 14/4 15/3
RPF biopsy 10 (55%) 11 (61%)
Constitutional symptoms 16 (89%) 13 (72%)
Pain (abdominal, lumbar) 16 (89%) 17 (94%)
Ureteral involvement 14 (78%) 13 (72%)
Randomised trial of prednisone and tamoxifen in idi opathic RPFBaseline characteristics of the randomised patients
Ureteral involvement 14 (78%) 13 (72%)
Unilateral 5/14 (36%) 3/13 (23%)
Bilateral 9/14 (64%) 10/13 (77%)
Acute renal failure 9 (50%) 9 (50%)
ESR, median (range)-mm/Ih 78 (10-122) 63 (8-120)
CRP, median (range)- mg/L 30.6 (0.6-63) 36.8 (4-182)
“Conservative” renal drainage (stents, nephrostomies)
9 (50%) 9 (50%)
Surgical ureterolysis 3 (17%) 4 (22%)
Time of recurrence (after randomisation)
Diagnosis of recurrence
Prednisone
Patient # 8 1st month Relapsing bilateral hydronephrosis
Prednisone Tamoxifen
Remission rate at the end of treatment
17/18 (94%) 11/18 (61%) 0.04
p value
Randomised trial of prednisone and tamoxifen in idi opathic RPFResults- Primary end-point
Tamoxifen
Patient # 2 3rd month Pain, raised ESR and CRP, RPF enlargement on CT
Patient # 17 5th month Relapsing unilateral hydronephrosis, lumbar pain
Patient # 12 7th month Constitutional symptoms, raised ESR and CRP
Patients # 5 and # 8 8th month Pain, relapsing unilateral hydronephrosis, raised ESR and CRP
Patient # 13 8th monthRelapsing bilateral hydronephrosis, raised CRP, RPF
enlargement on MRI
Patient # 10 8th monthPain, relapsing unilateral hydronephrosis, raised ESR, RPF
enlargement on CT
Randomised trial of prednisone and tamoxifen in idi opathic RPF
Treatment of recurrent disease
Treatment arm Treatment for recurrence Outcome
Prednisone
Patient #8 Stent placement; refused medical therapy active disease
Tamoxifen
Patient #28-month prednisone followed by
remissionPatient #28-month prednisone followed by
prednisone+methotrexate (currently taking)remission
Patient #56-month prednisone followed by
prednisone+methotrexate (currently taking)remission
Patient #8 Stent placement (lost to follow-up)
Patient #10 9-month prednisone remission
Patient #129-month prednisone followed by
prednisone+methotrexate (currently taking)active disease
Patient #13 Surgical ureterolysis plus 8-month prednisone remission
Patient #17 Surgical ureterolysis remission
Relapses afterthe end of treatment
4/17 (23.5%) 2/11 (18.2%) 0.99
Randomised trial of prednisone and tamoxifen in idi opathic RPFResults- Secondary end-points
Recurrences during 1/18 (5.5%) 7/18 (38.9) 0.04the treatment
Prednisone Tamoxifen p value
Relapses occurred at 1 and 6 months after treatment withdrawal in the Tamoxifen group, and 4, 6, 18, and 31 months after treatment withdrawal in the Prednisone group.
All post-treatment relapses were successfully treated by resuming corticosteroids, alone or in combination with methotrexate
Follow-up (months), median (range) 38 (9-73) 37 (12-78)
40
60
80
100
120
% re
sidu
al R
PF
PDN
TXF
onset
Randomised trial of prednisone and tamoxifen in idi opathic RPFResults- Secondary end-points
0
20
onset 4th month 8th month
4°month
8°monthEvolution of idiopathic RPF in a patient treated with prednisone
Randomised trial of prednisone and tamoxifen in idi opathic RPFResults- Secondary end-points
Treatment-related toxicity
Prednisone Tamoxifen
• 1 new-onset diabetes
• 3 worsened pre-existing diabetes
• 1 vertebral collapse
• 4 hypertension
• 1 new-onset diabetes
• 2 hypertension
• 1 acute myocardial infarction
• 11 hypercholesterolemia
• 1 acute myocardial infarction
• 16 hypercholesterolemia
• 11 weight gain >5 kg
• other common steroid-related side-effects
• 3 weight gain >5 kg
• 1 vaginal bleeding
• 1 reduced libido
Ongoing trial: methotrexate as steroid-sparing agen t in idiopathic RPF
Diagnosis of idiopathic RPF
Randomisation
Prednisone 1 mg/kg/day (1 month)
PREDNISONE PREDNISONE (0.25 mg/kg/day)+ PREDNISONE (0.5 mg/kg/day)
PREDNISONE (0.25 mg/kg/day)+ MTX (0.3 mg/kg/week)
CT/MRI (4th month)
Post-treatment follow-up: 16 months
CT/MRI (8th month)
8 months prednisone tapering
prednisone tapering
8 months
Treatment of idiopathic RPF: proposed algorithm
Vaglio A, Salvarani C, Buzio C. Lancet 2006
Cancro della mammellaCancro della mammella
Tumori desmoidiTumori desmoidi
Induratio penisInduratio penis
TAMOXIFENE
Uso terapeutico Effetti avversi
Cancro endometrio*Cancro endometrio*
Miomi uteriniMiomi uterini
EndometriosiEndometriosi
CheloidiCheloidi
Cicatrici ipertroficheCicatrici ipertrofiche
Polipi uteriniPolipi uterini
Irregolarità mestrualiIrregolarità mestruali
TromboemboliaTromboembolia
Infarto miocardico
Colesterolo
*RR: 1,5 per <2 anni di terapiaRR: 2 per 2-5 anni di terapiaRR: 6,9 > 5 anni di terapia
Gelmon K. .Lancet 2000;356:868-9
Treatment of idiopathic RPF: unresolved issues
Idiopathicretroperitoneal
fibrosis
Autoimmune thyroiditis
Psoriasis
Ankylosingspondylitis
ANCA+vasculitis
Steroids + CYC/MTX/MMF Steroids alone
Moroni G, et al. Nephrol Dial Transplant 1999; LeBlanc CM et al. Arthritis Rheum 2002; Vaglio A, et al. Rheumatology (Oxford) 2008; Vaglio A, et al. Am J Med 2003; Famularo G, et al. Scand J Rheumatol 2008
fibrosis
Membranousnephropathy
Rheumatoidarthritis
Tamoxifene
Proteina kinasi C Transforming growth factor Transforming growth factor ββββββββ1 (TGF 1 (TGF ββββββββ1 )1 )
Fibroblasti
Macrofagi, fibroblasti,linfociti, cellule endoteliali
AngiogenesiAngiogenesi
Proliferazione fibroblastiProliferazione fibroblasti
Sintesi del collageneSintesi del collagene
Connettive tissue growth factor (CTGF)
Potenzia TGF Potenzia TGF ββ11
Stabilizza TGF Stabilizza TGF ββ11
Proliferazione fibroblastiProliferazione fibroblasti
Sintesi del collageneSintesi del collagene
Prednisone vs Tamoxifen in Idiopathic Retroperitone al FibrosisResults- Secondary end-points
Renal outcome and inflammatory markers
Serum creatinine (mg/dL), median (range)
Residual hydronephrosis
Prednisone Tamoxifen p value
1.1 (0.7-2.0) 1.1 (0.6-1.9) 0.53
(N, %)
ESR (mm/Ih), median (range)
CRP (mg/L), median (range)
1 (5.5%)
18.3 (1-64)
4.67 (0.3-15)
5 (28%)
23.1 (4-61)
6.86 (1.1-31)
0.09
0.39
0.33
40
60
80
100
120
% re
sidu
al R
PF
PDN
TXF
onset
Prednisone vs Tamoxifen in Idiopathic Retroperitone al FibrosisResults- Secondary end-points
0
20
onset 4th month 8th month
4°month
8°monthEvolution of idiopathic RPF in a patient treated with prednisone
Prednisone vs Tamoxifen in Idiopathic Retroperitone al FibrosisCONCLUSIONS
• Prednisone is more effective than tamoxifen in maintaining disease remission in patients with idiopathic RPF
• The high relapse rate observed after steroid withdrawal (23%) in patients who achieved sustained remission may suggest that a longer treatment course is warranted
• Given the pronounced steroid-related toxicity, the role of other • Given the pronounced steroid-related toxicity, the role of other immunosuppressants (e.g. methotrexate) as steroid-sparing agents needs to be investigated
Retroperitoneal fibrosis: definition and general fe atures
Retroperitoneal fibrosis (RPF) is characterised bya fibro-inflammatory tissue which usuallysurrounds the abdominal aorta and the iliacarteries , and often causes ureteral obstructionand involvement of the inferior vena cava.
The idiopathic form of RPF is a rare disease,usually occurring in middle-aged adults (40-60yrs), with a M:F ratio of 2:1
Idiopathic RPF has an unclear etiology, but itspathogenesis is probably autoimmune.
As many autoimmune diseases, idiopathic RPFalso has a chronic-relapsing clinical course.
Idiopathic retroperitoneal fibrosis and the spectru m of chronic periaortitis
Vaglio A, Salvarani C, Buzio C. Lancet 2006
Parums DV. Histopathology 1990
Prednisone vs Tamoxifen in Idiopathic Retroperitone al FibrosisResults- Secondary end-points
Post-treatment relapses
Prednisone Tamoxifen
Relapses after the end of treatment
4/17 (23.5%) 2/11 (18.2%) 0.99
p value
Follow-up (months), median (range)
38 (9-73) 37 (12-78)
Relapses occurred at 1 and 6 months after treatment withdrawal in the Tamoxifen group, and 4, 6, 18, and 31 months after treatment withdrawal in the Prednisone group.
All post-treatment relapses were successfully treated by resuming corticosteroids, alone or in combination with methotrexate
One patient (treated with Tamoxifen), without evidence of relapse, progressed to ESRD and started hemodialysis (72 months after diagnosis of RPF).
median (range)
Time of relapse (after treatment)
Diagnosis of relapse
Prednisone
Patient #
Prednisone Tamoxifen
Relapse rate afterthe treatment
4/17 (23.5%) 2/11 (18.2%) 0.99
p value
Randomised trial of prednisone and tamoxifen in idi opathic RPF
Tamoxifen
Patient #
Patient #
Patient #
Patients # and #
Patient #
Patient #
Randomised trial of prednisone and tamoxifen in idi opathic RPF
Treatment of relapse disease
Treatment arm Treatment for relapse Outcome
Prednisone
Patient #
Tamoxifen
Patient #Patient #
Patient #
Patient #
Patient #
Patient #
Patient #
Patient #
Treatment of idiopathic RPF: unresolved issues
Thrombosis of the inferior vena cava and renal veins
Should prophylactic anticoagulation bealways recommended?
Which symptoms/signs should promptanticoagulation?
Renal artery stenosis
Palmisano A, et al. submitted
Renal artery stenosis
Should all patients be screened usingrenal angiography or angio-MRI?
Should “silent” renal artery stenoses betreated using angioplasty or stents?
Treatment of idiopathic RPF: unresolved issues
Involvement of the thoracic aorta and its branches
A distinct disease subset?
Should we monitor thoracic vessel disease during the whole follow-up?
A B
C
D
Thoracic vessel involvement
YES NO p value
No. of pts 14 27 n.s.
Age, median (range)- yrs 61 (43-75) 54 (32-82) n.s.
Female gender, n (%) 8 (57.1%) 6 (22.2%) 0.03
Type of CP (IRF/IAAA) 2/11 1/25 n.s.
E
GF
Type of CP (IRF/IAAA) 2/11 1/25 n.s.
ESR, median (range)- mm/h 91 (51-112) 73 (47-100) n.s.
CRP, median (range)- mg/L 28.5 (11.1-45) 27 (14,1-85,7) n.s.
Positive ANA, n (%) 4/14 (28.6%) 6/21(28.6%) n.s.
No. (rate) of relapses 8 (57.1%) 7 (25.9%) 0.04
with thoracic involvement
without thoracic involvement
p = 0.29
Vaglio A, et al. American College of Rheumatology Meeting 2008 (Abstract 634, S400)