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


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


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


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


prednisone+methotrexate (currently taking)remission

Patient #8 Stent placement (lost to follow-up)

Patient #10 9-month prednisone remission


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


0

20

onset 4th month 8th month

4°month

8°monthEvolution of idiopathic RPF in a patient treated with prednisone


Treatment-related toxicity


• 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


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


Post-treatment relapses


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 #


Relapse rate afterthe treatment

4/17 (23.5%) 2/11 (18.2%) 0.99

p value


Tamoxifen

Patient #

Patient #

Patient #

Patients # and #

Patient #

Patient #


Treatment of relapse disease

Treatment arm Treatment for relapse Outcome

Prednisone

Patient #

Tamoxifen

Patient #Patient #

Patient #

Patient #

Patient #

Patient #

Patient #

Patient #


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?


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)

2009 Convegno Malattie Rare Buzio [23 01]

Health & Medicine

Transcript of 2009 Convegno Malattie Rare Buzio [23 01]