Year In Review: VasculitisPers Cailin Sibley, M.D., M.H.S. Director, Vasculitis Clinic April 27 th, 2018 NTEREST DISCLOSURE Disclosures none Learning Objectives Describe new medications for the treatment of vasculitis Develop an approach for using these medications Update knowledge on risks of diseases and medications used to treat these diseases Describe treatment targets which will be evaluated over the next several years 1
Outline Large vessel vasculitis: pathogenesis, imaging, treatment ANCA vasculitis: complications, treatment Others: IgA vasculitis, Behçet s GCA: Is It caused by Herpes Zoster? Rationale Nagel et al, JAMA Neurol, 2015 GCA: Is It caused by Herpes Zoster? Retrospective cohort study in 2 large databases: Medicare and Truven Health Analytics MarketScan *** 3.1% and 6% had preceding HZ events England et al, Arthritis Rheumatol, Dec 2017 2
GCA: Is It Caused by Herpes Zoster? nested case control study using an electronic database from the UK Rhee et al, Ann Rheum Dis, June 2017 GCA: Is It Caused by Herpes Zoster? Rhee et al, Ann Rheum Dis, June 2017 Conclusions 1) Intriguing biopsy data re VZV are not backed up by large population studies 2) Data support the role of infectious triggers, but likely not a single type 3
Imaging in Large Vessel Vasculitis Ultrasound to Diagnosis GCA If clinical suspicion is high, a positive ultrasound is sufficient for diagnosis Steroids > 7 days decrease utility of ultrasound Caveat: all readers underwent specific training for imaging in large vessel vasculitis Monti et al, Rheumatology, Jan 2018 Halo Sign 4
Imaging To Assess Disease Activity In Large Vessel Vasculitis: FDG PET Suggestion that patients with LVV and positive PET in clinical remission are at higher risk for future flares. Many patients with inactive disease have a positive PET Grayson et al, Arthritis Rheum, March 2018 EULAR Recommendations for Imaging in LVV 1) In patients with suspected GCA, an early imaging test is recommended to complement the clinical criteria for diagnosing GCA, assuming high expertise and prompt availability. Imaging should note delay treatment. LoE: 1 LoA: 9.2 (2.1) 2) In patients in whom there is a high clinical suspicion of CGA and a positive imaging test, the diagnosis can be made without a biopsy. In patients with low clinical suspicion and negative imaging, the diagnosis can be considered unlikely. Otherwise, additional efforts are needed. LoE: 2 LoA: 9.4 (1.0) 3) Ultrasound of temporal +/ axillary arteries is recommended as the first imaging modality in a patients with suspected cranial GCA. A noncompressible halo sign is most suggestive of GCA LoE: 1 LoA: 9.7 (0.6) 4) High resolution MRI of cranial arteries to investigate mural inflammation may be used as an alternative for GCA diagnosis if ultrasound is not available or is inconclusive. LoE: 2 LoA: 9.2 (1.1) Dejaco et al, Ann Rheum Dis, Jan 2018 EULAR Recommendations for Imaging in LVV: MRI, CT, PET 1) CT and PET are not recommended for the assessment of inflammation of cranial arteries. LoE 5 LoA 9.5 (1.2) 2) Ultrasound, PET, MRI and/or CT may be used for detection of mural inflammation and/or luminal changes in extracranial arteries to support the diagnosis of LV GCA. Ultrasound is of limited value for assessment of aortitis LoE 3 (PET / MRI) 5 (CT) LoA 9.8 (0.6) 3) In patients with suspected TAK, MRI to investigate mural inflammation and/or luminal changes should be used as the first imaging test to make a diagnosis of TAK LoE 3 LoA 9.1 (1.4) 4) Conventional angiography is not recommended for the diagnosis of GCA or TAK as it has been superseded by the previously mentioned imaging modalities LoE 5 LoA 9.8 (0.6) Dejaco et al, Ann Rheum Dis, Jan 2018 5
Treatment in Large Vessel Vasculitis GiACTA Study: Tocilizumab for LVV Inclusion Criteria: Age > 50, diagnosis of active GCA (biopsy or imaging), elevated ESR RCT 2:1:1:1 tocilizumab 162mg weekly + 26 week steroid taper tocilizumab 162mg every other week + 26 week steroid taper placebo + 26 week steroid taper placebo + 52 week steroid taper Stone et al, NEJM, July 2017 GiACTA Study: Tocilizumab for LVV Primary endpoint: percentages of patients with sustained prednisone free remission at week 52 Remission: absence of flare and the normalization of the CRP concentration to less than 1 mg per deciliter Flare: Clinical signs + ESR > 30 and need to treat with prednisone Sustained remission: Remission from weeks 12 52 Stone et al, NEJM, July 2017 6
GiACTA Study: Tocilizumab for LVV Stone et al, NEJM, July 2017 Poll: In What Patients Would you Use Tocilizumab? (A)All patients with GCA (B)Patients with refractory disease (C) Patients at risk for complications from steroids (D) B+ C (E) Never I don t believe the data or I want more data (F) Never it s too expensive Abatacept for LVV: Giant Cell Arteritis 49 patients, open label followed by randomized withdrawal in responders Steroid taper to off over 28 weeks * Significant difference Langford et al, Arth Rheum, April 2017 7
Abatacept for LVV: Takayasu Arteritis 34 patients * Nonsignificant difference Langford et al, Arth Rheum, April 2017 JAK Inhibitors: Are They Next in LVV? Human GCA Artery Engrafted to Mouse Zhang et al, Circulation, Dec 2017 Small Vessel Vasculitis: Treatment 8
Novel Treatment in AAV: C5a Receptor Inhibitor Avacopan Rationale Mouse Model of MPO Antibody Induced Glomerulonephritis Requires C5aR activation Schreiber et al, JASN, 2009 Novel Treatment in AAV: C5a Receptor Inhibitor Avacopan Inclusion Criteria: Newly diagnosed or relapsing AAV RCT of induction (CYC or RTX) plus standard prednisone 60 avacopan + prednisone 20 avacopan alone without prednisone Primary outcome: change in BVAS Jayne et al, JASN, April 2017 Novel Treatment in AAV: C5a Receptor Monoclonal Ab Avacopan Jayne et al, JASN, April 2017 9
Novel Treatment in AAV: C5a Receptor Inhibitor Avacopan Prednisone 60 Jayne et al, JASN, April 2017 How Long Should We Be Treating AAV With Maintenance Rituximab? MAINRITSAN 48 Month Follow Up Efficacy Safety Karras et al, Ann Rheum Dis, Oct 2017 What is the Safety of Continued Rituximab Infusions in ANCA Vasculitis? IgG levels are stable long term Cortazar et al, Arth Rheum, May 2017 10
Effect of Induction Regimen on Malignancy Risk in AAV? 323 patients seen at a single tertiary care center (Addenbrooke s Hospital, Cambridge, UK) from 2000 2014 SIR matched for sex and age Van Daalen et al, Ann Rheum Dis, June 2017 IV vs oral cyclophosphamide? Single center retrospective observational study Majority of deaths (12/22) due to infection Caveat: Oral cyclophosphamide group sicker 98% with renal involvement vs 46% in iv group La Crette et al, Clin Rheumatol, Dec 2017 Cardiovascular Events in AAV: Meta analysis of Current Data Houben et al, Rheumatology, Sept 2017 11
Mepolizumab for EGPA (Churg Strauss) Inclusion Criteria: Relapsing or refractory EGPA. Only 5 patients with GN or alveolar hemorrhage Methods: RCT of mepolizumab (IL 5 blockade) 300 mg q 4 weeks vs placebo in 136 patients Primary Outcome: Accrued weeks of remission (BVAS 0 on prednisone <= 4 mg) and proportion in remission at weeks 36 and 42 Wechsler et al, NEJM, May 2017 Mepolizumab for EGPA Wechsler et al, NEJM, May 2017 Rituximab for EPGA Retrospective study of 41 patients with EGPA Sicker population with higher rates of kidney disease Remission defined as BVAS = 0 Mohammad et al, Ann Rheum Dis, 2016 12
Rituximab Also Works for IgA Vasculitis Open label study of 22 patients with refractory disease Maritati et al, Arthritis Rheum, Jan 2018 Back to Behçet s. Dietary Triggers of Behçet s Volle et al, Arthritis Care Res, Sept 2017 13
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