Paradoxial Safety Signals from Biologics

Transcription

1 Paradoxial Safety Signals from Biologics Christopher Ritchlin, MD, MPH Professor of Medicine Director, Translational Immunology Research Center University of Rochester Medical Center Rochester, NY Disclosures Consultant Amgen Abbot Janssen UCB Pfizer Research Amgen Abbot Janssen UCB

2 Overview Cutaneous and autoimmune reactions to TNFi Pathogenesis Therapeutic approach Cutaneous reactions

3 Cutaneous lesions reported with TNFi More common Psoriasiform Palmopustular Vulgaris Scalp psorasis Intersitial granulomatous dermatitis Acute generalized exanthemaous pustulosis (AGEP) Lupus-like lesions Scattered report Sweet s Syndrome Vasculitis Guttate psoriasis Psoriasiform lesions: phenotype 114 Case Reports Underlying disorder: RA, SpA, IBD, Behcets dx Pustular 52%, Plaque 50%, guttate 15% Observed with all TNFi No causative infection, new drug introduction, stress or recent trauma identified Collamer et al. Arthritis Care Res,2008;59(7):996

4 Potential etiologies of TNFi induced psoriasis Underlying disease PsA and not RA or AS Systemic infection-chlamydia, steptococcus Reactive arthritis Drug-induced lesions Lupus Acute Granulomatous Exanthematous Pustolosis Intersititial granulomatous Acute generalized exanthematous pustulosis (AGEP) Halevy S. Current Opinion in Allergy and Clinical Immunology 2009, 9:

5 Interstitial granulomatous dermatitis Observed in SLE, RA, vasculitis and LP disorders Variable appearance: plaques, cords on trunk or extensor surfaces Observed after exposure to TNFi Deng A. Archives Derm 2006;142:198 Palmopustular psoriasis Most common in female smokers Not associated with Cw6 alleles Often resistant to therapy

6 Guttate psoriasis Tear drop lesions Associated with B23, B17 and Cw6 2 weeks after strep infection Plaque psoriasis Associated with Cw6 alleles Early and late onset Most common phenotype in the population Many psoriasiform lesions can mimic psoriasis vulgaris

7 Lupus-like Reactions to TNFi Incidence of Lupus-like reactions to TNFi: a French national survey, Arthritis Research and Therapy, cases of DIL in 866 pts in French Biologics Registry -(10 with skin disease, 12 with systemic disease) -Mean onset of symptoms occurred at 9 months in the Infliximab group and 4 months in the Etanercept group -8 patients required steroids (IV/oral/topical) -Median time for symptoms to resolve was 8 weeks (except for one) -Incidence of occurrence was 0.19% with Infliximab and 0.18% with Etanercept De Bandt M. Arthritis, Research and Therapy, 2005

8 Features of patients with ATIL Summary of data from 4 studies BSBR n=41 Costa et al (USA) n=33 Ramos Casal et al (Spain) n=71 De Bandt et al (France) n-12 Manifestation % N=158 Positive ANA 72 Immunologic Abn (anti-dsdna Ab) 65 Discoid rash 61 Hematologic Abn (cytopenias) 27 Arthritis 30 Serositis 9 Photosensitivity 5 Renal 5 Williams E. Rheumatology 2009;48:716 Autoantibody Profiles in ATIL Williams E. Rheumatology 2009;48:716

9 Pathogenesis Four arms of immune homeostasis and disease Banchereau J et al. Immunity 2004;20:539

10 Pathophysiology of Psoriasis Clark RA, Kupper TS. J Clin Inv 2006(8):2084 Proposed mechanisms of ATIL Shift to an IFN signature and Th2 profile-il-10 TNF induced necrosis of cells that release nuclosomes TNFi may interfere with apoptosis of cells and clearance of nuclear debris Decline in TREGs Sarzi-Puttini P Autoimmunity. 2005;38:507 D Auria F. J int Med. 2004;255:409 Schur, P. et al Drug-Induced Lupus, Up-to-date, 2012

11 IFN inducible proteins observed in TNFi associated psoriasis TNFi Vulgaris Epidermal myxovirus resistance Protein (MxA) De Gannes GC Arch Derm 2007;143(2):223 Effect of IL-12/23i and TNFi on psoriasiform lesions CD4+CD45RB(high)CD25- (naive CD4) T cells Ma, HL. Arthritis Rheum 2010;62(2):430

12 IL-17, 21, 22 mrna increase after TNFi Ma, HL. Arthritis Rheum 2010;62(2):430 TNF blockade associated with a decline in TREG cells Ma, HL Arthritis Rheum 2010;62(2):430

13 Rx of SS pts with ETN induced IFN signature and BAFF DBRCT of of 20 SS pts treated with ETN for 12 weeks Mavragani CP. Arthritis Rheum 2007;56(12):3995 Treatment

14 Collamer A. et al Arth Care Res 2008;59(7):996 Stop the TNFi Treatment of ATIL in most cases, the manifestations will clear in 4 to 8 weeks For patients who persist with features of SLE, corticosteroids or immunosuppressants may be required.

15 Overview Cutaneous and autoimmune reactions to TNFi Pathogenesis Therapeutic approach