Disclosures. Silk Road. Oral Ulceration 10/28/2013. Behçet s Syndrome: An Enigma Revisited

Size: px

Start display at page:

Download "Disclosures. Silk Road. Oral Ulceration 10/28/2013. Behçet s Syndrome: An Enigma Revisited"

Harriet Austin
5 years ago
Views:

Disclosures Behçet s Syndrome: An Enigma

ongoing clinical study As no medications to

medications discussed are off-label usages

Study Group for Behçet s Disease 1990 Oral

yr) plus two of the following - Recurrent

1 Disclosures Behçet s Syndrome: An Enigma Revisited Cailin Sibley, M.D., M.H.S. Oregon Health & Science University October 8 th, 2013 Dr. Sibley receives anakinra from Sobi for an ongoing clinical study As no medications to treat Behçet s disease are FDA approved all medications discussed are off-label usages Silk Road Diagnostic criteria International Study Group for Behçet s Disease 1990 Oral Ulceration Recurrent oral ulcers (at least 3 / yr) plus two of the following - Recurrent genital ulcers - Eye lesions (uveitis or retinal vasculitis) - Skin lesions (E nodosum, papulopustular lesions or acneiform lesions) - Positive pathergy test 1

2 Eye Disease Eye Disease Posterior Uveitis Active vitritis (+3 haze OU) Normal retina and fluorescein angiogram Retinal vascular leakage veins>>arteries with cotton wool spots H. Nida Sen, NEI H. Nida Sen, NEI Hypopyon Uveitis Pathergy H. Nida Sen, NEI Pustular Skin Disease Gastrointestinal Disease Heller and Bagi, NIDDK 2

3 Neurologic Disease Vascular Disease Superficial Thrombophlebitis Al-Araji and Kidd, Lancet Neurol, 2009 Vascular Disease Papulopustular Lesions Seen More Frequently in Patients with Arthritis Arterial Aneurysm Deep Vein Thrombosis Diri et al, Ann Rheum Dis, 2001 Acne arthritis enthesopathy Increased enthesopathy scores in BS patients with acne and arthritis Treatment?? No significant increase the frequency of sacroiliitis or HLA B27 Hatemi et al Arthritis Rheum 2008 Verity et al. Br J Ophthalmol 2003; 87:

Skin and mucosa Arthritis Eye DVT Aneurysms Gastrointestinal Neurologic Topical agents, Colchicine Azathioprine IFNα a-tnf Colchicine Azathioprine a-tnf Steroids and azathioprine Steroids and AZA AZA

4 Skin and mucosa Arthritis Eye DVT Aneurysms Gastrointestinal Neurologic Topical agents, Colchicine Azathioprine IFNα a-tnf Colchicine Azathioprine a-tnf Steroids and azathioprine Steroids and AZA AZA + CYC-A IFNα a-tnf Steroids, AZA or CYC or CYC-A Steroids, AZA or SAZ or thalidomide or a-tnf Steroids and AZA or IFN or CYC or MTX or a-tnf a-tnf EULAR Recommendations for the Management of BD Hatemi et al. Ann Rheum Dis; 2008 Open Label Study of Gevokizumab (IL-1b antibody) in Resistant Behçet s Uveitis Inclusion Criteria Diagnosed with Behçet disease Acute posterior or panuveitis and/or retinal vasculitis Resistant to azathioprine and/or ciclosporin Exclusion Criteria More than 10 mg of prednisolone or equivalents within the previous month of the study Gul et al, Ann Rheum Dis, 2012 Open Label Study of Gevokizumab (anti- IL-1b antibody) in Resistant Behçet s Uveitis Colchicine and immunosuppression withdrawal. Gevokizumab 0.3 mg/kg infusion Repeat infusion allowed if first effective Gevokizumab Demographics Day 0 Day 28 or later Primary Endpoint: Progression of uveitis from day 0 to day 28 Prednisolone 10mg or less allowed throughout study. Prednisolone <= 80mg allowed for rescue therapy Gul et al, Ann Rheum Dis, 2012 Gul et al, Ann Rheum Dis, 2012 Gevokizumab Clinical Results Gul et al, Ann Rheum Dis, 2012 Apremilast (PDE4 Inhibitor) in Mucocutaneous Disease: Major Inclusion and Exclusion Criteria Inclusion Criteria 18 years of age Diagnosed with Behçet disease Exclusion Criteria Any active major organ involvement of Behçet disease Pregnant or breast-feeding Have active ulcer disease (oral and/or genital) in the History of certain infection 28-day period before or congenital or acquired screening immunodeficiency Have 2 oral ulcers at the time of randomization Courtesy of Yusuf Yazici and Gulen Hatemi 4

Mean Number of Oral Ulcers Randomization 10/28/2013 Apremilast (Phosphodiesterase 4 Inhibitor) in Mucocutaneous Disease: Trial Design Prerandomization Phase Screening Treatment Phase Study Day

5 Mean Number of Oral Ulcers Randomization 10/28/2013 Apremilast (Phosphodiesterase 4 Inhibitor) in Mucocutaneous Disease: Trial Design Prerandomization Phase Screening Treatment Phase Study Day Extension Phase Observational Follow-up Phase* Apremilast 30 mg BID Apremilast 30 mg BID Followup Placebo Courtesy of Yusuf Yazici and Gulen Hatemi Apremilast: Demographics Placebo (n=56) Apremilast 30 mg BID (n=55) Total (N=111) Age, years: Mean (median) 34.7 (34.0) 34.3 (34.0) 34.5 (34.0) Min, max 18, 64 19, 59 18, 64 Sex, n (%): Male 18 (32.1) 16 (29.1) 34 (30.6) Female 38 (67.9) 39 (70.9) 77 (69.4) Race, n (%): White 55 (98.2) 53 (96.4) 108 (97.3) Black 0 2 (3.6) 2 (1.8) Other 1 (1.8) 0 1 (0.9) Region, n (%): Turkey 53 (94.6) 50 (90.9) 103 (92.8) USA 3 (5.4) 5 (9.1) 8 (7.2) Weight, kg: Mean (median) 68.7 (67.3) 67.3 (68.0) 68.0 (68.0) Min, max 45.0 (99.0) 44.0 (95.0) 44.0 (99.0) Courtesy of Yusuf Yazici, M.D. Apremilast: Primary End Point Mean ulcers at week 12 was 0.5 with apremilast and 2.1 with placebo (P<0.0001) All patients in the PBO group switched to APR from week 12 visit APR was discontinued at week 24 Future Directions / Clinical Trials Ocular Disease: - AIN457 (anti- IL-17a). Terminated. - Gevokizumab Phase III wk0 wk2 wk4 wk6 wk8 wk10 wk12 wk14 wk16 wk18 wk20 wk22 wk24 wk26 wk28 Placebo mg BID Mucocutaneous Disease: - Abatacept - Anakinra - Tocilizumab Courtesy of Gulen Hatemi, M.D. Case Study #1 64 yo Caucasian woman with Behçet s (oral ulcers, anterior uveitis, folliculitis) presenting with resistant oral ulcers. Ulcers began 3y ago, increasing in number with some ulcers present for over a year. Skin pustules over buttocks with small blisters over her chest. Oral ulcers and anterior uveitis steroid and azathioprine responsive. PMH: fatty liver, osteopenia, glaucoma, gallstones Meds: colchicine 0.6, azathioprine 200, prednisone 5 5

Case Study #2 25 yo HLA B51+ Caucasian woman with Behçet s

Still with recurrent skin nodules, steroid responsive PMH:

Diagnostic Criteria in American Patients NIH / NYU /

98 Prevalence = 5 / 100,000 = 0.2% Behçet s in the US vs.

* * * # 1751 1937 Hulusi Behcet observed intracellular

6 Case Study #2 25 yo HLA B51+ Caucasian woman with Behçet s (oral ulcers, genital ulcers, nodular skin lesions) seen at NIH for second opinion. No ocular, GI, neurologic involvement. Still with recurrent skin nodules, steroid responsive PMH: celiac sprue, seizure disorder, pyelonephritis Meds: azathioprine 150, colchicine 1.8, prednisone 25 All: many Positive Predictive Value of Diagnostic Criteria in American Patients NIH / NYU / Istanbul Collaboration Sensitivity = 0.95 Specificity = 0.98 Prevalence = 5 / 100,000 = 0.2% Behçet s in the US vs. Turkey Infection Virus? * * * # Hulusi Behcet observed intracellular inclusions from hypopyon fluid 1953 virus isolated from ocular fluid cause BS like symptoms when injected into animals. (Sezer) 1957 virus isolated from brain tissue (Evans) * ANOVA p < 0.05 Could not be replicated 6

Serum antibodies to Streptococcus sanguinis higher in Behcet s patients (Yokata et al,

T-cell hyperreactivity to bacteria (Mochizuki et al, Eur J of Immunol; Hirohata et al, Cell

- Pustular skin lesions are not sterile (Hatemi et al, Annals Rheum Dis, 2004) Patients

susceptibility loci in the HLA region in Behçet s disease # 1879 Verity et al.

7 Infection Bacteria? - Poor oral health is correlated with disease severity (Mumcu et al, Oral Diseases, 2006) - Serum antibodies to Streptococcus sanguinis higher in Behcet s patients (Yokata et al, Microbiology and Immunology, 1992) Bacterial 16S rrna Sequencing Tissue Punch Biopsies - T-cell hyperreactivity to bacteria (Mochizuki et al, Eur J of Immunol; Hirohata et al, Cell Immunol, 1992, Kurauchi et al, FEMS Immunol, 2005, Hirohata et al, Clin Exp Immunol, 1998) - Pustular skin lesions are not sterile (Hatemi et al, Annals Rheum Dis, 2004) Patients Controls Julie Segre, NHGRI HLA B51 Prevalence Identification of multiple independent susceptibility loci in the HLA region in Behçet s disease # 1879 Verity et al. Br J Ophthalmol 2003; 87: Hughes et al, Nat Genetics, 2013 GWAS Turkish Patients Manhattan Plot GWAS IL-10 IL-23R Regions Remmers et al, Nat Gen, 2010 Remmers et al, Nat Gen,

GWAS Japanese Patients IL-10 IL-23R Regions GWAS with Imputed Genotypes IL-10 IL-23R Mizuki et al, Nat Gen, 2010 Kirino et al, Nat Gen, 2013

HLAB MICA variant IL23R STAT4 ERAP1 CCR1 KLRC4 PSORS1C1 Environment Location? Bacteria? Virus p = 0.

a-il-6 Behcet s is a SYNDROME Take Home Points Treatment should be targeted at organ manifestations Novel therapeutic options Genetics give

pathogen sensing are likely important Acknowledgements NIAMS Clinical Fellows, Elizabeth Joyal, Nikki Plass, Deborah Stone, Dawn Chapelle,

8 GWAS Japanese Patients IL-10 IL-23R Regions GWAS with Imputed Genotypes IL-10 IL-23R Mizuki et al, Nat Gen, 2010 Kirino et al, Nat Gen, 2013 Deep Resequencing of Nonsynonymous Variants C-alpha test meta-analysis p = 6.09 x 10-5 p = Pathogenesis Model Genes IL10 HLAB51? HLAB MICA variant IL23R STAT4 ERAP1 CCR1 KLRC4 PSORS1C1 Environment Location? Bacteria? Virus p = TLR4 NOD2 a-tnf PDE4 inhib Inflammation Interferon-a a-il-1 Kirino et al, PNAS, 2013?Co-stimulation blockade? a-il-6 Behcet s is a SYNDROME Take Home Points Treatment should be targeted at organ manifestations Novel therapeutic options Genetics give clues to risk factors Pathogens vs. pathogen sensing are likely important Acknowledgements NIAMS Clinical Fellows, Elizabeth Joyal, Nikki Plass, Deborah Stone, Dawn Chapelle, Bahar Afshar, Yin Liu, Gina Montealegre, Raphaela Goldbach-Mansky NIDDK Theo Heller, Preet Bagi NEI Hatice Nida Sen, Robert Nussenblatt NHGRI Melissa Meredith NIDCR Dean Aria, Sharon Gordon NCI Ed Cowen NINDS Frank Anderson Clinical Center Robert Wesley NYU Yusuf Yazici University of Istanbul Gulen Hatemi, Hasan Yazici 8

$TNF Inhibitors Multicenter Study of Infliximab for Refractory$ 2012 Disease Activity Comparison Interaction between HLA B51

0001 n=35 n=77 n=107 n=35 n=77 n=107 * ANOVA p = 0.

067 Scores worse in women (BDQOL) Older patients (BDCAF)

ethnic backgrounds (BDCAF, BSAS) Kirino et al, Nat Gen, 2013

9 TNF Inhibitors Multicenter Study of Infliximab for Refractory Uveoretinitis in Behçet Disease Okada et al, Arch Ophthalmol, 2012 Disease Activity Comparison Interaction between HLA B51 and ERAP1 * ANOVA p = < n=35 n=77 n=107 n=35 n=77 n=107 * ANOVA p = n = 26 n = 107 ANOVA p = Scores worse in women (BDQOL) Older patients (BDCAF) Patients from the United States (BDCAF) Patients with atypical ethnic backgrounds (BDCAF, BSAS) Kirino et al, Nat Gen, 2013 Oral Tissue mrna Sequencing - GSEA Oral Tissue mrna Sequencing - GSEA ES 0.57 NES 1.44 Nominal p-value 0.06 ES 0.72 NES 1.45 Nominal p-value

Behçet s Disease: The American Perspectivecan Pers. Disclosures. Learning Objectives 4/16/2018

Behçet s Disease: The American Perspectivecan Pers Cailin Sibley, M.D., M.H.S. Director, Vasculitis Clinic April 27 th, 2018 NTEREST DISCLOSURE Disclosures As no medications to treat Behçet s disease are