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
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
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
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
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”
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
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
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
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
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.
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
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
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