Retroperitoneal Fibrosis -- Current Challenges and ... · Retroperitoneal Fibrosis -- Current...

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Retroperitoneal Fibrosis -- Current Challenges and Opportunities for Biologics Carmen E. Gota MD Center for Vasculitis Care and Research Department of Rheumatology Cleveland Clinic Cleveland, OH case 50 yo, F back pain, nausea, vomiting CRP 3.2 mg/dl creatinine 1.12 mg/dl hemoglobin 9.7 g/dl CT abdomen: concentric irregular retroperitoneal soft tissue thickening surrounding abdominal Ao below the origin of SMA; severe narrowing of the left renal vein

Transcript of Retroperitoneal Fibrosis -- Current Challenges and ... · Retroperitoneal Fibrosis -- Current...

Page 1: Retroperitoneal Fibrosis -- Current Challenges and ... · Retroperitoneal Fibrosis -- Current Challenges and Opportunities for Biologics Carmen E. Gota MD ... malignancies retroperitoneal

Retroperitoneal Fibrosis --

Current Challenges and Opportunities for Biologics

Carmen E. Gota MD

Center for Vasculitis Care and Research

Department of Rheumatology

Cleveland Clinic

Cleveland, OH

case

• 50 yo, F

• back pain, nausea, vomiting

• CRP 3.2 mg/dl

• creatinine 1.12 mg/dl

• hemoglobin 9.7 g/dl

• CT abdomen: concentric irregular

retroperitoneal soft tissue

thickening surrounding abdominal

Ao below the origin of SMA;

severe narrowing of the left renal

vein

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case: CT of abdomen: right hidronephrosis, compression

of left renal vein

Albarran-Ormond-Gerota syndrome

Joaquin Albarran (1860-1912) .

Retention rénale par periurétérité.

Libération externe de l’uretère.

Association française d'urologie,

1905

John K. Ormond (1886-1978): Bilateral ureteral obstruction due to envelopment and compression by an inflammatory retroperitoneal process.

Journal of Urology, Baltimore, 1948, 59: 1072-1079. J. K. Ormond: Idiopathic retroperitoneal fibrosis: a discussion of the etiology.

Journal of Urology, Baltimore, 1965, 94: 385-390.

Jean Casimir Felix Guyon (1831-1920)

Dimitrie Gerota(1867-1939) “Gerota’s fasciitis” - Romanian

doctor- documented the presence of the anterior renal fascia also

called Gerota fascia

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John Kelso Ormond Bilateral ureteral obstruction due to envelopment and

compression by an inflammatory retroperitoneal process. Journal of Urology, Baltimore, 1948, 59: 1072-1079.

2 cases, both men, in their 40s with bilateral ureteral obstruction found to have a retroperitoneal plaque-like mass. One died of renal obstruction, the other survived with ureterolysis.

Ormond’s first description

• a dense greyish fibrous

retroperitoneal mass

• surrounded the Aorta

• compressed (but not

invaded) the ureters

which were enveloped

in mass), and IVC

Ormond J K. J Urol 1948; Mitchinson MJ. J Clinical Path 1970

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Ormond syndrome = retroperitoneal fibrosis=chronic periaortitis

• Chronic periaortitis

– inflammation in the Ao

– originating in the outer layers

of the Ao

– irrespective of the size of the

Aorta

• Inflammatory Ao aneurysm

– inflammatory periaortitis

with Ao dilatation

Vaglio A. Current Opinion Rheumatol 2011; Walker DI. Br J Surgery 1972

Aorta Aorta

retroperitoneal fibrosis – clinical presentation

• incidence 1/mil

• prevalence: 1.38/100k

• age: 52-58

• gender: ♂:61-81%

• general symptoms (37-88%):

• fever, weight loss fatigue

• local symptoms (79-89%):

– back pain (32-38%)

– flank pain (27-42%)

– abdominal pain (28-40%)

• hydronephrosis ( 50-95%)

• aortic aneurysmal dilatation (4-17%)

• WSR ↗ (50-92%)

• CRP↗ (78-79%)

• location of RPF other than around the

aorta: periureteral, periiliac,

retrovesical, paracolic, porta hepatis,

tail of pancreas

Uibu T. Lancet 2004; Brandt AS.. J Urol 2011; Fernandez –Codina A. Clin Rheumatol 2013; Li KP. Clin Rheum 2011; Kermani T. Mayo Clin Proc 2011; Corradi D. Kidney Int 2007; Baker LRI.Br J Urol 1988; Lugosi M. Rev de Med Int 2013; HA YJ .J Korean Med Sci 2011; Gomez Garcia I. Scand J Urol Nephrol 2012

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pathology

Mitchinson MJ. J Clinical Path 1970

Path review of 40 cases- extension of mass:

• aorta: fibrosis around the aorta, follows the course of common iliac arteries

• inferior extension: unusual below the pelvic brim

• lateral extension: draws the ureters towards the aorta with little other lateral extension; the right ureter can be fixed in the groove between the IVC and Ao

• superior extension: variable extent, usually up to renal arteries but up to mediastinum, some reports of entire Ao

• anterior extension: into the small bowel mesentery-rare but possible; displacement of the duodenum; nfiltration of the pelvic mesocolon-rare

pathology

Mitchinson MJ. J Clinical Path 1970; Sakata N. Am J Surg Path 2008; Vaglio A. Curr Op Rheumatol 2011; Vaglio A. Am J Med. 2003

changes in the aortic wall: • intima: marked fibrous thickening • media-adventitia: marked mononuclear cell

inflammation and fibrosis, often lymphoid follicles

• vasa vasorum: infiltration around the vasa vasorum of the adventitia and outer media, sometimes frank necrotizing vasculitis, endarteritis obliterans, obliterative phlebitis

changes in the surrounding soft tissues: the fibrous tissue in all cases showed one of two patterns: • collagen bundles interspersed with

inflammatory cells • “ old looking” acellular serial biopsies in 2 patients showed

that the more active type of inflammation matured into the “older type”

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pathology The inflammatory component:

• small lymphocytes: T and B cells

• macrophages

• plasma cells

• eosinophils

Corradi D. Kidney International 2007

The fibrous component: • spindle shaped cell proliferation

• extracellular collagen

pathogenesis

Alberti C. Eur Rev Med Pharmacol Sci 2007; Mitchinson MK. J Clin Pathol 1970; Vaglio A. Curr Op Rheumatol 2011; Uibu T. Lancet 2004;Mantorana D. Arthr Rheum 2006;Boiardi L. Rheumatology 2011

atheroscolerosis ox-LDL macrophagesadventitial lymphs when media is breached

Ao aneurysm pulsed load stress, perianeurysmal blood products

smoking, asbestos

immunogenetic HLA-DRB1*03, CCR5 polymorphysms shift to Th2 response

vasculitic inflammation vasavasorum, media adv Ao

trauma abdominal surgery

persistent infections

local spread , TB,

drugs, radiotheraphy

ergot alkaloids, bromcriptine, beta blockers, hidralazine, methyldopa, carbegoline, pergolide, aspirin, paracetamol, amphetamines

malignancies retroperitoneal malignancy desmoplastic or paraneoplastic reaction

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pathogenesis

retroperitonea fibrosis and IGG4 – related systemic disease

TIMELINE OBSERVATION

Hamano H. NEJM 2001

AIP=autoimmune sclerosing pancreatitis serum IgG4 levels ↗, while controls and pts with chronic pancreatitis, PBC, PSC or Sjogren did not. IgG4 levels decreased after GC therapy

Kamisawa T J. Gastroenterol 2003; Am J Surg Path 2004

IGG4-related systemic disease: Immunohistochemistry: all AIP patients moderate or severe IgG4+ plasma cells assocated with CD8+ T cells, in peripancreatic retroperitoneal tissue, bile duct, GB, portal area of the liver, gastric, colonic mucosa, salivary glands, lymph nodes, bone marow, pancreas- few IGG4+ cells in same sites in controls

Umehara H. Mod Rheumatol 2012 Khosrosharhi A. Curr Op Rheumatol 2011

CONSENSUS • various organs • men, middle age, elderly • effectively tx with steroids • infiltration with IgG4+ plasma cells • elevated IgG4 in serum(≥x2) • lymphoplasmacytic infiltration • irregular fibrosis • obliterative phlebitis

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retroperitoneal fibrosis and IgG4

Retroperitoneal fibrosis - IgG4:

– 10-59% of RPF cases

– IgG4/IgG plasma cell ratio:≥ 30 (40), or

IgG4+ plasma cells per hpf ( one study

13 vs 1);

– predominantly men

• Inflammatory aortic aneuryms:

– 4-12% I TAA, 40-57% IAAA

– IgG4+ plasma cell per hpf >50

Zen Y .Am J Surg Path 2009; Vaglio A. Lancet 2011; Clevelanger J. Human Pathology 2012; Yamashita K. Histopathology 2007; Khosroshahi A. Medicine 2013; Kasashima S. Am J Surg Path 2008; Kasashima S. Vasc Surg 2009; Raparia K. Int J Clin Exp Pathol 2013; Laco J. Cardivasc Pathol 2011; Kasashima S. J Vasc Surg 2010; Stone J. Arth Care Res 2010; Sakata N. Am J Surg Path 2008; Siddiquee Z Cardiovascular Pathol 2012; Lighaam LC. Int J Rheumatol 2012; Nirula A. Curr Opin Rheumatol 2011; Neild GH.BMC Medicine 2006

Unanswered questions: 1. clinical significance 2. impact on prognosis and

therapy 3. IgG4+ deposition also

reported in infections, atherosclerotic aneurysms

4. true prevalence? – evidence for steroid induced disappearance of IgG4 staining

inflammatory aortic aneurysm and IgG4

Kasashima S. Am J Surg Pathol 2008; Stone J.Arthritis Rheum 2009

IgG4+ lymphoplasma-

cytic aortitis- lymphoid

aggregates in media and adventitia

many plasma cells and

eosinophils

obliterative phlebitis in adventitia

inflammatory cells infiltrate along nerve

fascicles

immunohisto-chemistry showing IgG4+ plasma cells in adventitia

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role of imaging in RPF

Malignant RF Idiopathic RF

age older?

shape of mass lobulation, nodularity plaque like

location higher in retroperitoneum extension above the renal arteries

distal to renal arteries

Ao dispacement wider fibrosis behind the Ao, anterior displacement of Ao

ureteral displacement

no displacement or lateral displacement

medial displacement

Mirault T. Malignant retroperitoneal fibrosis Medicine 2012; Degesys GE. AJR 1983

1. Extent of disease, and periaortic tissue involvement 2. Allow to follow treatment response 3. Help to identify inflammatory status 4. Diffentiate from other conditions, in particular

infections, and malignancies

role of PET in RPF

Jansen I. European J of Internal Medicine 2010; Salvarani C. Arthritis and Rheumatism 2005; Moroni G. Eur J Nucl Med Mol Imaging 2012; Bertagna F. Jpn. J Radiol 2012; Nakajo M. J Comput Assist Tomogr 2007; Treglia G. Rheumatol Int 2013; Piccoli GB. Nephrol Dial Transplant 2010; Vaglio A. Clin Exp Rheumatol 2005

baseline positive PET : 77-100% problems with PET: • lack of standardization • lack of clear definitions of remission/partial remission

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treatment

medical

glucocorticoids

colchicine

tamoxifen

DMARDs

biologics

surgical

ureteral stents

ureterolysis

open aortic aneurysm repair

endovascular aortic aneurysm repair

surgical repair of inflammatory aortic aneurysms- impact on periaortic fibrosis

Paravastu SCV. European J Vascular Endovascular Surgery 2009

• review off all studies with 1 year CT follow up = 56 studies

• complete regression of peri aortic inflammatory process – in only 38%

• a significant number of patients undergoing open aneurysm repair showed regression of hydronephrosis compared to the endovascular procedure

• it is unclear if endovascular surgery has benefit on hydronephrosis because in half of the cases, regression was only noted after steroid initiation.

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medical treatment

Study N, treatment, outcomes

Moroni G Nephrol Dial Transpl 2006

83%-100% remission , 17, 1 year, all received GC, ( T, Aza, sx)

Marcolongo R Am J Med 2004

96% resolution of sx and urinary obstruction: 26

patients, 1year, all GC + Aza /CTX; failure rate 1/100 patient year

Fernandez-Codina A Clin Rheum 2013;

87% ”good evolution” ; 19, 1 year, all GC

Kermani T Mayo Clin Proc 2011

• 9% complete resolution, 54% improved on imaging, 34% stable, 3% progression; 12% relapse, 7.3% died

• 63% of stents were removed • GC stopped in half, ¾ were still taking medications; 151 patients, median follow up 1 year, 63% GC mostly with other

drugs (T, DMARDs)

tamoxifen

study outcome

Jansen I Eur J Int Med 2010

58% -successful treatment (such a clinical, laboratory and

radiological improvement); 26 pts, T dose?

Van Bommel EFH Ann Int Med 2006

79%- resolution of symptoms in 2.5 weeks; 75%-CT

improvement; 16% ≥ 50 % improvement on CT; 19, T 40

mg/day

Van Bommel EFH Eur J Int Med 2012

treatment success: 65%; 78%- CT scan size regression (@8

mo); 17% - hydronephrosis-cases resolved; 55 pts, T 40

mg/day x 2 years

Vaglio A Lancet 2011

randomised open label remission maintenance study:

all 40 patients received prednsione 1 mg/kg for a month 18

Prednsione taper vs 18 Tamoxifen 2.5 mg/kg/day x 8 months all patients were in remission, including removal of stents when present. relapse rate 5% Prednisone vs 33% Tamoxifen

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biologics in RPF

Biologic agent Data

Rituximab • 10 cases of IgG4 RD, of which 3 IgG4 inflammatory periaortitis: 90% marked clinical improvement at 1 month, all stopped steroids and DMARDs,serum IgG4 levels dropped, a rise predicted relapse

• 2 cases of IAAA who failed GC decrease in mass, removal of ureteral stents

Infliximab • 1 RPF case failed GC, MTX Infliximab x 3 years improvement in imaging findings

Tocilizumab • 1 case of ITAA and RPF clinical and laboratory response, improvement in PET/CT

Koshroshahi A. Medicine 2012; Maritati F. Ann Rheum Dis. 2012; Catanoso MG. Clin Exp. Rheumatol. 2012; Catanoso Mg. Tocilizumab- A novel therapy for patients with large vessel vasculitis abstract 2011 ACR meeting

why consider biologics?

• Inflammatory infiltrate with activated B and T cells: • T cells -CD3+, CD4+, CD8+ , B cells- CD 20+; plasma cells,

macrophages, and eosinophils • Th1 and Th2 activation: gene transcripts from molecular

analysis of Ao biopsies: IFN-gamma, IL-1, IL-2, IL-4 • Evidence for Th2 type reaction:

• In IgG4+ cases rise in IL-10 • CCR 5 -polymorphism assocated with non functional CCR 5

on Th1 lymphs shift to Th2 • Role of IL-6:

• Elevated levels of IL-6 in patients with chronic periaortitis compared to controls

• ox-LDL adventitial macrophagesTNF-alfa NFkB controls monocyte activation via IL-6

• IL-6 activated T cells increase in IL-21 increase in IgG4 production by plasma cells

Corradi D. Kidney International 2007; Ramshaw AL. J Clin Pathol 1994; Boiardi L Rheumatology 2011; Brasier AR.

Cardivascular Res 2010; Moroni G Kidney Int 2005; Carbone G. Int J Biol Sci 2013

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unmet needs

• understanding of the pathogenetic process that triggers

inflammation and fibrosis

• clear definition of remission /partial remission/flare

• prospective randomized controlled studies

• exploration of the role of biologic agents as steroid sparing

drugs