Article - JDDonline - Journal of Drugs in Dermatology

Daniel Opel MA,^a Afrodite Economidi MD,^b Daphne Chan PhD,^c Yasmine Wasfi MD PhD,^cSameer Mistry BSc MB ChB MRCS,^d Theognosia Vergou MD,^b Christina Antoniou MD PhD,^band Howard Sofen MD^e
^aLoyola University Chicago Stritch School of Medicine, Chicago, IL ^bPsoriasis Clinic, Department of Dermatology, University of Athens, A. Sygros Hospital, Athens, Greece ^cDepartment of Immunology, Janssen Research & Development, LLC, Spring House, PA ^dDepartment of Medical A7airs, Janssen-Cilag Ltd, Buckinghamshire, UK ^eDermatology Research Associates, Los Angeles, CA

Abstract

Background: Patients with psoriasis who are treated with systemic and biologic therapies may have an increased risk of infections, including hepatitis B virus (HBV). Cytokines that modulate CD4+ T cell subsets, including interleukin (IL)-12 and IL-23, have been suggested to play a role in the pathogenesis of HBV infection.
Objective: To report the first known cases of acute HBV infection in 2 ustekinumab-treated patients with psoriasis from a phase 3 (PHOENIX 1) and a phase 4 (TRANSIT) study.
Results: Both ustekinumab-treated patients generated an immune response toward HBV and experienced typical courses of infection, without progression to chronic HBV infection.
Conclusion: Continued monitoring of liver-related adverse events in clinical trials, registries, and spontaneous reporting from the postmarketing setting will further contribute to understanding the role of ustekinumab in viral hepatitis.

J Drugs Dermatol. 2012;11(12):1498-1501.

INTRODUCTION

Immunomodulatory therapies for psoriasis may predispose patients to an increased risk of new infections or reactivation of latent infections, such as tuberculosis,^1,2 herpes zoster,^3,4 and viral hepatitis.^5,6 Because patients with active and chronic infections are typically excluded from clinical studies, little is known about the epidemiology and pathophysiology of hepatitis infections in patients with psoriasis who are receiving biologic therapies. Two recent studies in Taiwan, where the hepatitis B virus (HBV) is endemic, reported a higher prevalence of HBV infection in patients with psoriasis than in the general population.^7,8

While the cytokine biology of HBV in patients with psoriasis is not completely understood, cytokines involved in psoriasis may be implicated in the pathophysiology of viral hepatitis.⁹ Tumor necrosis factor α (TNF-α) and interleukin (IL)-12 can modulate the clearance and control of HBV by suppressing viral replication.^10,11 Therefore, patients treated with anti-TNF or anti-IL-12 therapies may be at increased risk of new or reactivated HBV infections. Cases of HBV reactivation have been reported in anti-TNF-treated patients with concurrent chronic HBV and inflammatory diseases.^5,10,12-16 Ustekinumab treatment in a patient with psoriasis with chronic HBV was recently reported; no HBV reactivation was observed.¹⁷ There are currently no reported cases of acute HBV infection associated with anti-IL-12/23 therapy.

Ustekinumab (Stelara^®; Janssen Biotech, Inc, Horsham, PA) is a human, anti-IL-12/23 monoclonal antibody approved for the treatment of moderate to severe psoriasis. The efficacy and safety of ustekinumab has been demonstrated in more than 4,000 patients,^18-28 with up to 5 years of follow-up.²⁵ Here we describe the first known reports of acute HBV infections in 2 ustekinumab-treated patients from 2 clinical trials.^19,26

Case #1

Patient #1 was a 33-year-old white man from the phase 3 PHOENIX 1 study,¹⁹ with a 12-year history of moderate to severe psoriasis and an otherwise uncomplicated medical history. At baseline, the patient's disease was severe, with 77% body surface area involvement and a Psoriasis Area and Severity Index (PASI) score of 46. Prior treatments included topical steroids, ultraviolet B, psoralen plus ultraviolet A, and acitretin. The patient had an HBV risk factor of a same-sex relationship.²⁷ Because infection history was selfreported, blood samples collected at baseline were retrospectively analyzed and were negative for HBV viral DNA.

The patient received ustekinumab 90 mg in March 2006 (week 0), with 2 induction doses 4 weeks apart, followed by maintenance dosing every 12 weeks. By week 8, total clearance of psoriasis was achieved, with 100% improvement from baseline in PASI score (PASI 100). No adverse events were reported, and liver enzyme levels were within normal limits through week 16. At week 20 (36 days following the last dose), significant, transient elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported (Figure 1). Alkaline phosphatase and total bilirubin levels were also elevated 1 to 2 weeks later. Liver synthetic function, as assessed by serum albumin,