Vasculitis Update. A selective review of what s new. Dr Jonathan Akikusa MBBS FRACP

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1 Vasculitis Update A selective review of what s new Dr Jonathan Akikusa MBBS FRACP Consultant Paediatric Rheumatologist Royal Children s Hospital, Melbourne Honorary Research Fellow Murdoch Children s Research Institute February 2016

2 Nosology in Paediatric Vasculitis ANCA in vasculitis Emerging entities

3 Chapel Hill Nomenclature 1994 Large vessel vasculitis Giant cell (temporal) arteritis Takayasu arteritis Medium-sized vessel vasculitis Polyarteritis nodosa Kawasaki disease Small vessel vasculitis Wegener s Granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Henoch-Schonlein purpura Essential cryoglobulinemic vasculitis Cutaneous leukocytoclastic angiitis

4 Current classification criteria of childhood vasculitis (EULAR/PRES) Predominantly large vessel vasculitis Predominantly medium vessel vasculitis Predominantly small vessel vasculitis Granulomatous Non-granulomatous Other vasculitides Ozen et al. Ann Rheum Dis 2006;65:

5 Current classification criteria of childhood vasculitis (EULAR/PRES) Predominantly large vessel vasculitis Takayasu arteritis Predominantly medium vessel vasculitis Childhood polyarteritis nodosa Cutaneous polyarteritis Kawasaki disease

6 Current classification criteria of childhood vasculitis (EULAR/PRES) Predominantly small vessel vasculitis Granulomatous Wegener s Granulomatosis Churg-Strauss syndrome Non-granulomatous Microscopic Polyangiitis Henoch-Schonlein purpura Isolated cutaenous luekocytoclastic vasculitis Hypocomplementic urticarial vasculitis

7 Current classification criteria of childhood vasculitis (EULAR/PRES) Other vasculitides Behcet disease Cogan syndrome Isolated vasculitis of the central nervous system Vasculitis secondary to infection, malignancies, drugs Vasculitis associated with connective tissue diseases Unclassified

8 Chapel Hill nomenclature 2013 Jennette JC et al. Arthritis Rheum 2013;65(1):1-11

9 EULAR/PRES cwg classification criteria ) Histopathology - Vascular/ Perivascular Granulomatous inflammation 2) Upper airway involvement - Chronic nasal discharge, nasal septum perforation, sinus disease, saddle nose 3) Laryngo-tracheo-bronchial involvement - subglottic, tracheal or bronchial stenosis 4) Pulmonary involvement - nodules, cavities, fixed infiltrates 5) Renal involvement - Proteinuria, haematuria, pauci-immune necrotizing GN 6) ANCA panca/mpo or canca/pr3

10 ANCA and disease behaviour ANCA specificity more predictive of relapsing disease in AAV than diagnostic label (GPA/ MPA/ Renal limited disease) All KLD MPA GPA Lionaki et al. Arthritis Rheum (10):

11 ANCA and disease behaviour Future directions in AAV nomenclature Lionaki et al. Arthritis Rheum (10):

12 ANCA and disease behaviour ANCA specificity broadly correlates with disease manifestations Lionaki et al. Arthritis Rheum (10):

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14 Vasculitis as the presenting feature of Autoinflammatory disease

15 Adenosine Deaminase 2 (ADA2) Described by 2 groups (NIH, Israel) in 2014 Mutation in CECR1 resulting in reduction in ADA2 Early onset recurrent fevers, onset lacunar strokes, livedoid rash and systemic vasculopathy/vasculitis mimicking PAN Biopsies with changes consistent with reduced endothelial integrity, endothelial activation and inflammation Some changes in B- cells: fewer memory B cells in peripheral blood, modest reduction in terminal differentiation of B cells and Ig-secreting cells after T-cell-dependent stimulation. Zebra fish model - intracranial bleeding in embryos, hypothesis ADA2 is a growth factor for endothelial and leukocyte development

16 ADA 2 * Images deleted Zhou Q et al. N Engl J Med 2014;370: Elkan PN et al. N Engl J Med 2014;370:921-31

17 Adenosine Deaminase 2 (ADA2) Updated data from NIH cohort at 2015 ACR 16 patients Livedo racemosa a constant feature 12/16 stroke (9/12 before 5 years) - Haemorrhagic and ischaemic Lacunar (small subcortical, deep brain nuclei and brainstem) None with changes on MRA of cerebral vasculitis Haematologic abnormalities common (anaemia, leukopenia, thrombocytopenia) Hypogammaglobulinemia ~50% All treated with anti TNF-a drugs (either etanercept/ adalimumab) Improvement in APRs and FBE in majority None with stroke POST anti-tnf a treatment

18 Adenosine Deaminase 2 (ADA2) Data from Netherlands February /10 patients in Netherlands/Belgium homozygous for R169Q mutation Mean age presentation 2.6yr (0-8yr) Widely varying presenting phenotype and course HSM (8/9), Neurologic (8/9, 6 with MR changes) and skin (8/9) symptoms common Arthrlagia, anaemia, skin ulceration, stroke, cytopenias and heptatosplenomegaly, recurrent viral infections Hypogammagloblinemia (8/9) and cytopenias (9/9) also common Initial working diagnoses XLP-like disease, atypicial Diamond Blackfan, Storage disease, PAN, atypical cutaneous AML, HLH, CID with lymphoproliferation and autoimmunity ADA2 levels lower in those with stroke 3/9 had HCT with resolution of clinical/ laboratory abnormalities Van Montfrans et al. Rheumatology (Oxford) Feb 10. pii: kev439. [Epub ahead of print]

19 A20 haploinsufficiency Recently described (NIH) US/Canada/Turkey/ Holland Early onset disease resembling Bechet s disease Systemic inflammation associated with arthralgia/arthritis, oral and genital ulcers and ocular inflammation. Due to high-penetrance heterozygous loss-of-function germline mutations in TNFAIP3 A20 = NF-kB regulatory (inhibitory) protein May also be a negative regulator of NLRP3 inflammasome Zhou Q et al. Nat Genetics 2016;48:67-73

20 A20 haploinsufficiency Mean age at onset (Yr.) [Range] Sex (M:F) 7.1 [ ] 2:9 * Images deleted Clinical features Oral ulcers 100% Genital Ulcers 91% Ocular involvement 27% Uveitis (n) 3 Retinal vasculitis(n) 1 Autoantibodies Arthritis 45% Arthralgia 9% CNS disease 18% Pathergy 22% ANA 27% dsdna 9% RNP 9% LAC 27% acl 9% Zhou Q et al. Nat Genetics 2016;48:67-73

21 A20 haploinsufficiency Response to: Colchcine Prednisolone Infliximab Anakinra Many of the same agents used in Bechet s! Response to anakinra is interesting given possible role of A20 in the negative regulation of the NLRP3 inflammasome. Zhou Q et al. Nat Genetics 2016;48:67-73

22 STING-associated vasculopathy of infancy (SAVI) Mutation of TMEM173 resulting in GOF of Stimulator of Interferon Genes (STING) Onset in early infancy (1d-8 w) of systemic inflammation Significant acral cutaneous vasculopathy (fingers, toes, cheeks, ears, nose) Early-onset pulmonary fibrosis in some * Images deleted Liu Y et al. N Engl J Med 2014;371:507-18

23 Future directions