Psoriasis: Which Drug for Which Patient? Mark Lebwohl, MD

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1 Psoriasis: Which Drug for Which Patient? Mark Lebwohl, MD Sol and Clara Kest Professor And Chairman Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai

2 Disclosure Mark Lebwohl is an employee of Mount Sinai which receives research funds from: Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen / Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, Valeant and ViDac. Dr. Lebwohl is also a consultant for Allergan, Aqua Leo-pharma,and Promius.

3 DRUG PsA OBESITY CARDIAC CA +ANA LUPUS MS CROHN HEPATITIS C Ab + ETANERCEPT HBsAg+ Anti- HBc+ ADALIMUMAB INFLIXIMAB CERTOLIZUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB APREMILAST METHOTREXATE CYCLOSPORINE ACITRETIN

4 Drug-Induced SLE Associated with Etanercept Therapy 1 4 patients. Manifestations including fever, arthritis, discoid skin changes, rash, pleuritic pain, ANA, anti-dsdna, anti-histone, hypocomplementemia, anti-sm, anti-rnp. No baseline serologies. All resolved with discontinuation of etanercept and/or addition of corticosteroids. 1 Shakoor N et al. Lancet 2002;359(9306):

5 TNF- Inhibitor Induced Lupus Classic DILE 1 TNF-α inhibitor DILE 2 ANA >95% 100% dsdna <1% 91% Antihistone >95% 57% Decreased <1% 59% complement Rash 27% 72% 1. Benucci et al Clin Rheumatol 27: Zimmerman et al. Semin Arthritis Rheum: 2008 Jun;37(6):381-7

6 Regression of subacute cutaneous lupus erythematosus in a patient with rheumatoid arthritis treated with a biologic tumor necrosis factor alpha-blocking agent: comment on the article by Pisetsky and the letter from Aringer et al. Fautrel B, Foltz V, Frances C, Bourgeois P, Rozenberg S. Arthritis Rheum May;46(5):

7 Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Aringer M et al. Arthritis Rheum Oct;50(10): proteinuria, arthritis, C4 autoantibodies

8 Treatment of coexistent psoriasis and lupus erythematosus. Varada S, Gottlieb AB, Merola JF, Saraiya AR, Tintle SJ. J Am Acad Dermatol. 2015;72: Anti-TNF-α agents, ustekinumab, and abatacept may be valid treatment options for patients with concomitant LE and psoriasis. Clinical lupus flares in LE patients treated with TNF-α inhibitors were infrequent.

9 Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, pilot study. De Souza A, Strober BE, Merola JF, Oliver S, Franks AG Jr. J Drugs Dermatol. 2012;11:

10 A 2 year, open ended trial of methotrexate in systemic lupus erythematosus. Wilson K, Abeles M. J Rheumatol. 1994;21(9): Discoid lupus erythematosus: successful treatment with oral methotrexate. Goldstein E, Carey W. Arch Dermatol. 1994;130(7):938-9.

11 Hypertrophic lupus erythematosus treated successfully with acitretin as monotherapy. Al-Mutairi N, Rijhwani M, Nour-Eldin O. J Dermatol. 2005;32(6): Efficiency of acitretin in the treatment of cutaneous lupus erythematosus. Ruzicka T, Meurer M, Bieber T. Arch Dermatol. 1988;124(6):

12 Low dose cyclosporine A in the treatment of resistant proliferative lupus nephritis. Sheikholeslami M, et al. Mod Rheumatol. 2017:1-7 [Epub ahead of print]. Therapeutic drug monitoring of cyclosporine microemulsion in patients with corticosteroid-resistant systemic lupus erythematosus. Wada Y, et al. Mod Rheumatol. 2015;25(5):

13 TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1999;53: MS exacerbations with lenercept.

14 Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Mohan N, et al. Arthritis Rheum. 2001;44: etanercept, 2 infliximab partial or complete resolution on d/c 1 positive rechallenge

15 Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebocontrolled, randomised, dose-ranging study. Segal BM et al. Lancet Neurol 2008;7: UST no effect on MS

16 Activity of secukinumab, an anti-il-17a antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. Havrdová E, et al J Neurol. 2016;263:

17 Secukinumab, a human anti-il-17a monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Hueber W, Sands BE, et al Gut. 2012;61(12): Secukinumab not effective

18 No Definitive Role of Secukinumab in Crohn s Disease Entire treatment period exposure-adjusted (52 weeks) Potential involvement of IL-17 in Crohn s disease however published trials have not shown clinical benefit or disease exacerbation, consistent with Novartis Phase II in Crohn s Phase III incidence rate as expected with psoriasis No dose relationship between secukinumab doses All cases with Crohn s disease had prior history Based on all AEs AIN mg (n=1410) n (IR) [95% CI] AIN mg (n=1395) n (IR) [95% CI] Placebo (n=793) n (IR) [95% CI] Etanercept (n=323) n (IR) [95% CI] Inflammatory bowel disease 3 (0.26) [0.05, 0.75] 4 (0.35) [0.10, 0.90] 0 (0.00) [0.0, 1.83] 1 (0.34) [0.01, 1.90] Colitis ulcerative 2 (0.17) [0.02, 0.61] 2 (0.18) [0.02, 0.63] 0 (0.00) [0.0, 1.83] 1 (0.34) [0.01, 1.90] Crohn s disease* 0 (0.00) [0.0, 0.31] 2 (0.18) [0.02, 0.63] 0 (0.00) [0.0, 1.83] 0 (0.00) [0.0, 1.26] Anal fistula** 1 (0.08) [0.0, 0.47] 0 (0.00) [0.0, 0.32] 0 (0.00) [0.0, 1.83] 0 (0.00) [0.0, 1.26] IR=Exposure-adjusted incidence rate per 100 patient-years. A third case of Crohn s disease occurred in study A2211E1-150 mg Start of Relapse arm ** Not associated with inflammatory bowel disease

19 Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis. Lee SY, Jamal MM, Nguyen ET, Bechtold ML, Nguyen DL. Eur J Gastroenterol Hepatol. 2016;28: NO

20 Isotretinoin and inflammatory bowel disease: trial lawyer misuse of science and FDA warnings. Tenner S. Am J Gastroenterol. 2014;109: Isotretinoin, acne, and Crohn's disease: a convergence of bad skin, bad science, and bad litigation creates the perfect storm. Gastroenterol Hepatol (NY). 2013;9:752-5.

21 Etanercept therapy for patients with psoriatic arthritis and concurrent hepatitis C virus infection: report of 3 cases. Magliocco MA, Gottlieb AB. J Am Acad Dermatol. 2004;51(4): Etanercept monotherapy for a patient with psoriasis, psoriatic arthritis, and concomitant hepatitis C infection. Rokhsar C, Rabhan N, Cohen SR. J Am Acad Dermatol. 2006;54: Etanercept therapy in two patients with psoriasis and concomitant hepatitis C. De Simone C, Paradisi A, Capizzi R, Carbone A, Siciliano M, Amerio PL. J Am Acad Dermatol. 2006;54: Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with hepatitis C virus. Marotte H et al. Rheumatology (Oxford). 2007;46:97-9. Epub 2006 May 23.

22 Etanercept and Hepatitis C. Pritchard C. Journal of Clinical Rheumatology. 1999; 5: patient with rheumatoid arthritis & hepatitis C etanercept LFT's and viral titers d/c etanercept improved liver function

23 Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: a retrospective, multicentre study in a clinical setting. Navarro R. et al. Br J Dermatol. 2013;168(3): ETN (21), ADA (4), UST (4), IFX (2) HCV (20), HBV (5)

24 LFT s 2x in one pt (ETN) 2 pt s viral load during followup. 2pt s hepatocellular ca. (ETN) Biologic therapy was effective and safe for the majority of our patients with HCV and HBV infection Navarro R. et al. Br J Dermatol. 2013;168(3):

25 Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. Zein NN, for the Etanercept Study Group. Journal of Hepatology 2005;42: HCV, RNA was absent in 63% (12/19) etanercept patients, 32% (8/25) placebo patients. Patients receiving etanercept had lower frequency of most adverse events. liver bx regression of fibrosis: 6/11(55%) vs 2/6(33%)

26 Infliximab therapy for Crohn s disease in the presence of chronic hepatitis C infection. Campbell S, Ghosh S. Eur J Gastroenterol Hepatol. 2001;13: Hepatitis C: Infliximab No worsening of LFT s or vital titers by PCR.

27 Copied from 8/16/05

28 Induction of clinical remission with adalimumab-methotrexate combination therapy in a patient with rheumatoid arthritis and concomitant hepatitis C virus infection. Noguchi O, Gibo Y Mod Rheumatol. 2011;21: Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography. Frider B, Bruno A, Ponte M, Amante M. Case Reports Hepatol. 2013;2013: Use of tumor necrosis factor-alpha (TNF-alpha) antagonists infliximab, etanercept, and adalimumab in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: a retrospective record review of 11 patients. Li S, Kaur PP, Chan V, Berney S. Clin Rheumatol. 2009;28:

29 Two patients showed a transient elevation in AST and/or ALT from normal, but in all 11 patients, AST and ALT levels were within one time the upper range of normal at the conclusion of the study. No significant increase in viral load was seen except one patient who showed a fourfold increase from baseline. Use of these agents in patients with HBV or HCV may be associated with a transient transaminitis but appears to be safe overall. In both groups, frequent monitoring of serum transaminase levels and viral load is essential. Li S, Kaur PP, Chan V, Berney S.Clin Rheumatol. 2009;28:

30 The safety profile of ustekinumab in the treatment of psoriasis patients with concurrent hepatitis B or hepatitis C. Chiu, H-Y et al. Br J Dermatol 2013; 169: Reactivation of HCV and hepatocellular ca in 1/4 pts rx d with UST No in ALT, AST

31 Psoriasis treated with ustekinumab in a patient with hepatitis C. Abuchar A, Vitiello M, Kerdel FA. Int J Dermatol Mar;52(3):381-2.

32 Safety of Secukinumab in Hepatitis B Virus SL Bevans, TT Mayo, BE Elewski, in press Reports of HBV infection (5patients), HCV infection (3 patients), and HBV and HCV co-infection (1 patient), all without viral reactivation or significant elevation in liver enzymes.

33 Apremilast for a psoriasis patient with HIV and hepatitis C. Reddy SP, Shah VV, Wu JJ. J Eur Acad Dermatol Venereol doi: /jdv [epub ahead of print].

34 Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis. Ashton RE, Millward-Sadler GH, White JE. J Invest Dermatol 1982;79: hepatic fibrosis in 9/38(24%) after 5 years

35 Does cyclospsorine have a beneficial effect on the course of chronic hepatitis C infection after renal transplantation? Kamar N, Selves J, Sandres-Saune K, et al. Transplant Proc. 2006;38: HCV infection is not harmful to liver histology in more than 50% of renal transplant patients with grafts functioning more than 6 years. Cyclosporine might have beneficial effects on the natural course of HCV infection

36 Successful treatment with cyclosporine A of HCV-driven chronic liver disease mimicking autoimmune hepatitis in a patient with common variable immunodeficiency. Martire B, Gentile A, Francavilla R, et al. Immunopharmacol Immunotoxicol. 2005;27: Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Goto K, Watashi K, Murata T, et al. Biochem Biophys Res Commun. 2006;343:

37 Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins. Nakagawa M, Sakamoto N, Tanabe Y, et al. Gastroenterology. 2005;129: Specific inhibition of hepatitis C virus replication by cyclosporin A. Nakagawa M, Sakamoto N, Enomoto N, et al. Biochem Biophys Res Commun. 2004;313:42-7.

38 Cyclosporin A in chronic active hepatitis. Results of a pilot study of 20 patients. Friedrich K, Henning H. Z Gastroenterol 1988;26: Only 3 improved 1 case of hepatotoxicity of C s A

39 The role of different immunosuppression in the long-term histological outcome of HCV reinfection after liver transplantation for HCV cirrhosis. Papatheodoridis GV, Davies S, Dhillon AP, Teixeira R, Goulis J, Davidson B,Rolles K, Dusheiko G, Burroughs AK.Transplantation Aug 15;72(3): cyclosporine associated with recurrence & progression of hepatitis C -need for retransplantation in 10-25% of patients within 5 years

40 Reactivation of chronic hepatitis C after withdrawal of immunosuppressive therapy. Gruber A, Lundberg LG, Bjorkholm M. J Intern Med 1993;234: Activation of hepatitis C virus following immunosuppressive treatment. Yoshiba M, Sekiyama K, Sugata F, et al. Dig Dis Sci. 1992;37:478.

41 Effects of acitretin on the liver Roenigk HH Jr, Callen JP, Guzzo CA, Katz HI, Lowe N, Madison K, Nigra T, FiedlerVC, Armstrong RB. J Am Acad Dermatol 1999 Oct;41(4): No hepatotoxicity on liver bx after 2 yrs

42 DRUG PsA OBESITY CARDIAC CA +ANA LUPUS MS CROHN HEPATITIS C Ab + HBsAg+ Anti-HBc+ ETANERCEPT /- X + +* - +/-* ADALIMUMAB /- X + +* - +/-* INFLIXIMAB /- X + +* - +/-* CERTOLIZUMAB /- X + +* - +/-* USTEKINUMAB ?+/-*?/+* SECUKINUMAB + +? +/ X?/+*?+*?/+* IXEKIZUMAB + +? +/ X?/+*?+*?/+* BRODALUMAB + +? +/ X?/+*?+*?/+* GUSELKUMAB + +? +/ ??? TILDRAKIZUMAB??/+? +/ ??? RISANKIZUMAB??/+? +/ ??? MIRIKIZUMAB??/+? +/ ??? APREMILAST? +? +/ ?/+*?? METHOTREXATE + X X X X CYCLOSPORINE +/- +?/- X + +/ /-* X X ACITRETIN +/- +?/ ? X + + +

43 Which of the following treatments would be ideal for a patient with severe psoriasis, multiple sclerosis and Crohn disease? A) Certolizumab B) Brodalumab C) Acitretin D) Infliximab E) Ustekinumab

44 Reasons to Become a Registry Investigator Contribute to education/clinical knowledge of the psoriasis community Opportunity to establish a database of your patient population Academic recognition and publication opportunities Supplement existing insurance fee schedules Site compensation is $525 (including $25 for patient) per Enrollment visit and $350 (including $25 for patient) per biannual Follow Up visit

45 Become a Registry Research Investigator If you are interested in participating in the Psoriasis Registry as a research investigator, please psoriasis@corrona.org or visit or call