Retroperitoneal fibrosis from bedside to bench Augusto Vaglio, MD PhD UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma augusto.vaglio@virgilio.it
THE CONCEPT OF FIBRO-INFLAMMATORY DISEASES • Tumour-like, fibro-inflammatory lesions (fibrosis develops together with inflammation) • Inflammation is usually “chronic” • Organ damage due to inflammation and fibrosis • Organ damage due to compressive effects of newly formed fibro- inflammatory masses • Fibrosis in fibro-inflammatory diseases has the potential to regress after appropriate treatment
Sclerosing pancreatitis Sclerosing cholangitis Sclerosing mesenteritis Retroperitoneal fibrosis/chronic periaortitis Riedel’s and fibrosing Hashimoto’s thyroiditis Aortitis Mikulicz’s disease Inflammatory pseudotumour Fibrosing mediastinitis IDIOPATHIC
IgG4-RELATED Sclerosing pancreatitis Sclerosing pancreatitis Sclerosing cholangitis Sclerosing cholangitis Sclerosing mesenteritis Sclerosing mesenteritis Retroperitoneal Retroperitoneal fibrosis/chronic periaortitis fibrosis/chronic periaortitis Riedel’s and fibrosing Riedel’s and fibrosing Hashimoto’s thyroiditis Hashimoto’s thyroiditis Aortitis Aortitis Mikulicz’s disease Mikulicz’s disease Inflammatory pseudotumour Inflammatory pseudotumour Fibrosing mediastinitis Fibrosing mediastinitis IDIOPATHIC IDIOPATHIC
IgG4-RELATED Sclerosing pancreatitis Sclerosing pancreatitis Drug-related (methysergide, ergot-derivatives, pergolide) Sclerosing cholangitis Sclerosing cholangitis Sclerosing mesenteritis Sclerosing mesenteritis Gadolinium-induced fibrosis Retroperitoneal Retroperitoneal Infectious (TB, actinomycosis, fibrosis/chronic periaortitis fibrosis/chronic periaortitis histoplasmosis) Riedel’s and fibrosing Riedel’s and fibrosing Hashimoto’s thyroiditis Hashimoto’s thyroiditis Malignancies (lymphomas, sarcomas, solid tumours, Aortitis Aortitis inflammatory myofibroblastic tumour) Mikulicz’s disease Mikulicz’s disease Erdheim-Chester disease Inflammatory pseudotumour Inflammatory pseudotumour Fibrosing mediastinitis Fibrosing mediastinitis Other (trauma, Rx-therapy) IDIOPATHIC IDIOPATHIC SECONDARY
FROM RETROPERITONEAL FIBROSIS TO CHRONIC PERIAORTITIS
THE SPECTRUM OF CHRONIC PERIAORTITIS IDIOPATHIC RPF/NON-ANEURYSMAL CP ANEURYSMAL CP Vaglio A, Lancet 2006
Clinical presentation
CLINICAL MANIFESTATIONS Vaglio A, J Am Soc Nephrol 2016
CLINICAL MANIFESTATIONS Vaglio A, J Am Soc Nephrol 2016
CLINICAL MANIFESTATIONS Vaglio A, J Am Soc Nephrol 2016
Disease associations
ASSOCIATION WITH SYSTEMIC AUTOIMMUNE DISEASES Vaglio A, J Intern Med 2002; Lancet 2006
ASSOCIATION WITH ORGAN-SPECIFIC AUTOIMMUNE DISEASES CP patients Controls P value (n=73) (n=71) Age (years) 55.4 (10.6) 55.0 (9.6) 0.85 Male n (%) 46 (63) 41 (58) 0.52 TSH mIU/L 1.23 (0.79-1.70) 1.50 (1.07-2.59) 0.86 FT4 ng/dL 1.22 (0.20) 0.93 (0.18) <.0001 AbTPO positivity n (%) 18 (24.7) 7 (10.6) 0.03 AbTg positivity n (%) 12 (16.4) 5 (7.0) 0.11 Ultrasonographic evidence of HT n(%) 50 (69.4) 23 (32.4) <.0001 Thyroid volume (mL) 11.42 (5.31) 10.00 (4.43) 0.12 Thyroid nodules n (%) 18 (25.3) 24 (33.8) 0.27 Thyroid nodules diameter (mm) 14 (8-15) 10 (8-15) 0.77 Boby Mass Index (kg/m2) 26.90 (3.71) 27.44 (2.70) 0.38 Smoking (pack-years) 34.20 (26.20) 8.84 (10.32) <.0001 CIRS score 3 (2-5) 0 (0-1) <.0001 Ceresini G, Autoimmun Rev 2015
“DIFFUSE” (THORACO-ABDOMINAL) PERIAORTITIS 77 patients with chronic periaortitis (CP) 28 CP patients with thoracic vessel disease 7 (25%) thoracic 6 (21%) thoracic 15 (54%) aortic aneurysm aortic aneurysm thoracic plus periaortitis periaortitis 2 (7%) with 4 (14%) without 7 (25%) with 8 (29%) without epiaortic vessel epiaortic vessel epiaortic vessel epiaortic vessel involvement involvement involvement involvement Palmisano A, Rheumatology (Oxford) 2015
“DIFFUSE” (THORACO-ABDOMINAL) PERIAORTITIS Palmisano A, Rheumatology (Oxford) 2015
ASSOCIATION WITH OTHER FIBRO-INFLAMMATORY DISORDERS CD138 IgG4 IDIOPATHIC MEDIASTINAL FIBROSIS: 3 out of 9 cases in our series were associated with CP Rossi GM, Clin Rev Allergy Immunol 2016
ASSOCIATION WITH IgG4-RELATED (SYSTEMIC) DISEASE Kuttner’s RPF tumour of the parotid gland Tubulo- Sclerosing interstitial pancreatitis nephritis Palmisano A, Clin Nephrol 2010; Vaglio A, Rheum Dis Clin NA 2007; Saeki T, Kidney Int 2010
IgG4-RELATED DISEASE 1. Typical organ involvement (often tumour-like) 2. IgG4 >135 mg/dL 3. Tissue IgG4+ plasma cells >40% of IgG+ plasma cells and >10/hpf IgG4-related CP IgG4-unrelated CP Umehara H, Mod Rheumatol 2012; Corradi D, Cardiovasc Pathol 2016
SERUM IgG4 in CHRONIC PERIAORTITIS 800 700 600 550 500 IgG4 (mg/dL) 400 300 200 100 0 F D s s i l P C t o i R E t r r t / o n c s a o i m h c a t s a k y a p a h l o p T t l i o / a d A e e I C N H G Vaglio A, unpublished
IgG4-RELATED vs -UNRELATED CP No. IgG4+ cases, Criteria to differentiate Main findings pts n(%) IgG4+ vs IgG4- CP (in the IgG4+ subset) Castelein T, 17 9 (53) Serum IgG4 level Multifocal involvement, male 2015 predominance Kasashima S, 23 13 (56) Histology and IHC Higher incidence of autoimmune 2008 diseases Khosroshahi A, 23 13 (56) Histology and IHC Multifocal involvement 2013 Koo B, 2014 19 9 (47) Histology and IHC Higher relapse rate Yamashita M, 15 6 (30) Histology and IHC Multifocal involvement 2008 Zen Y, 2009 17 10 (59) Histology and IHC Multifocal involvement, male predominance Chronic Periaortitis IgG4-related IgG4-unrelated Rossi GM, Intern Emerg Med 2017
Immunopathogenetic model
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) TCR APC CD4+ T cell Aortic lumen Aortic wall Retroperitoneum
PATHOGENESIS: GENETIC ASSOCIATIONS • HLA DRB1*03 • CCR5 delta 32 • CCL11 haplotype • FcGR2A 308 cases 2443 controls ImmunoChip In collaboration with Ana Marquez & Javier Martín Martorana D, Arthritis Rheum 2006; Boiardi L, Rheumatology 2011; Mangieri D, Nephrol Dial Transplant 2012
PATHOGENESIS: ASBESTOS AND SMOKING Goldoni M, Ann Intern Med 2014
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) HLA- DR3 TCR CD4+ T cell Aortic lumen Aortic wall Retroperitoneum
ARCHITECTURAL ORGANISATION OF THE LYMPHOCYTE SUBSETS CD3 CD20 CD4 CD8 Corradi D, Kidney Int 2007
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) HLA- DR3 TCR CD4+ T cell Aortic lumen Aortic wall Retroperitoneum
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) CD20+ B cells HLA- DR3 TCR CD4+ T cell IL-6 Aortic lumen Aortic wall Retroperitoneum
INTERLEUKIN-6 IN CP p<0.0001 Vaglio A, Arthritis Rheum 2013
CP PATHOGENESIS: EOSINOPHILS, MAST CELLS AND EOTAXIN-1 Eosinophils Tryptase+ degranulating mast cells Eotaxin/CCL11 expression in retroperitoneal biopsies Mangieri D, Nephrol Dial Transplant 2012
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) CD20+ B cells fibroblasts HLA- DR3 TCR IL-6 CD4+ T cell IL-6 Aortic lumen Tryptase, eosinophil Eotaxin-1 Aortic wall granule proteins mast cells eosinophils
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental factors (asbestos, smoking) (Auto-)antigen (?) fibrocytes CD20+ B cells fibroblasts HLA- DR3 TCR IL-6 CD4+ T cell IL-6 Aortic lumen Tryptase, eosinophil Eotaxin-1 Aortic wall granule proteins mast cells eosinophils
FIBROCYTES Fibrocytes are a rare population of (circulating) precursors of tissue fibroblasts, which stain positive for CD45 and type I Col Type I col CD45 CD45 + ColI + cells in a CP biopsy
IMMUNOPATHOGENESIS OF CHRONIC PERIAORTITIS environmental IgG4+ plasma factors (asbestos, cells smoking) IL-4, IL 10, IL13 (Auto-)antigen (?) fibrocytes CD20+ B cells fibroblasts HLA- DR3 TCR IL-6 CD4+ T cell IL-6 Aortic lumen Tryptase, eosinophil Eotaxin-1 Aortic wall granule proteins mast cells eosinophils adapted from Vaglio A, J Am Soc Nephrol 2016
Treatment and outcome
GLUCOCORTICOIDS AS FIRST-LINE THERAPY Vaglio A, Lancet 2011
GLUCOCORTICOIDS AS FIRST-LINE THERAPY Vaglio A, Lancet 2011
TREATMENT OF RELAPSING DISEASE 16 consecutive relapsing CP patients MTX (15-20 mg/week) + PDN for 12 months (followed by observation or treatment continuation) Alberici F, Ann Rheum Dis 2013
RITUXIMAB FOR RELAPSING-REFRACTORY DISEASE Before Rituximab A B C After Rituximab D E F Maritati F, Ann Rheum Dis 2012
RITUXIMAB FOR CP • 16 patients with difficult-to-treat CP 12 relapsing-refractory 4 contraindications to standard-dose GCs • 14/16 had normal serum IgG4 • No one had evidence of (systemic) IgG4RD Urban ML, 54th ERA-EDTA congress Madrid 2017 (abstract)
TOCILIZUMAB FOR RELAPSING-REFRACTORY DISEASE Before and after Tocilizumab Vaglio A, Arthritis Rheum 2013
Recommend
More recommend
