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Infliximab-induced Psoria

Inflammatory Bo

Girish Hiremath, Lynn Duff

ABSTRACT

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23Gastroenterology, Hepatology, and NutritionI: 10.1097/MPG.0b013e3181f3d9abthese patients had any personal or family history of psoriasis. Amajority of our patients had CD (n 5 [83%]) and were girls (n 4[67%]). The median age for diagnosis of IBD was 13 years (mean13; range 1114), and the median age at which they were initiatedon infliximab was 15 years (mean 15; range 1316). At a median,our patients had received 15 doses (mean 13; range 617) ofinfliximab. The median duration of exposure to infliximab beforepresenting with psoriatic skin manifestation was 21 months (mean28, range 966) at a median infusion interval of 8 weeks (mean 8;

ceived April 30, 2010; accepted July 20, 2010.m the Inova Fairfax Hospital for Children, Falls Church, VA.dress correspondence and reprint requests to Girish Hiremath, MD,MPH, Inova Fairfax Hospital for Children, 3300 Gallows Rd, FallsChurch, VA 22042 (e-mail: girish.hiremath@inova.org).e authors report no conflicts of interest.pyright # 2011 by European Society for Pediatric Gastroenterology,Hepatology, and Nutrition and North American Society for Pediatricright 2011 by ESPGHAN and NASPGHAN. Unauthorized reprod0 JPGN Vose despite conventionaitiation of infliximabA total of 6 (8%) cases of IIP were identified (Table 1).ys a major role in clinical disease, stimulation of the immu-regulatory molecules, cellular proliferation, and apoptosis.

Among children, relentless clinical course, undesirableerse effects of steroids, an increased risk of steroid dependency,perianal disease may necessitate the use of antiTNF-a agents.plication of antiTNF-a agents, such as infliximab, has signifi-tly improved the management of IBD and other immune-diated disorders including psoriasis (3). Paradoxically, theree been reports of new-onset or exacerbation of psoriasis amongients with immune-mediated disorders and being managed withiTNF-a therapy. Occurrence of this paradoxical phenomenonbeen documented in adults with IBD. We report infliximab-nflammatory bowel disease (IBD) includes both Crohn disease(CD) and ulcerative colitis (UC) and is the most significantonic gastrointestinal disease affecting pediatric population inUnited States (1). The exact etiology for the chronic, inflam-tory, and relapsing course IBD is unclear. However, we knowt an excessive and poorly regulated T helper 1 response resultselevated levels of tumor necrosis factor-a (TNF-a), whichiximab is frequently used to treat both inflammatory bowel disease (IBD)

psoriasis. We reviewed the medical records of 73 children with IBD

eiving infliximab therapy and identified 6 (8%) cases of infliximab-

uced psoriasis. Five (83%) had Crohn disease and 4 (67%) were girls. The

riatic lesions appeared on the face (n 5; 83%) and perineum (n 1;). A median of 13 doses were administered during a median duration of

months. All of the patients were continued on infliximab to maintain

ical remission of IBD. Educating children with IBD and their caregivers

ut this paradoxical phenomenon and periodic dermatology evaluation

y promote patient care.

y Words: inflammatory bowel disease, infliximab, paradoxicalnomenon, psoriasis

GN 2011;52: 230232)sis in Children With

wel Disease

y, and Ian Leibowitz

uced psoriasis (IIP) in children with IBD and compare it to thein adults with IBD.

MATERIALS AND METHODS

udy Design and SubjectsThe present retrospective study was conducted in a suburban

ching hospital and was approved by the Inova Health Systemtitutional review board. Hospital records of children 18 years orunger at the time of initiation of infliximab therapy wereiewed. Only children diagnosed with IBD and receiving inflix-ab were included. Children receiving infliximab for other indica-ns were not considered for the analyses.

ta Collection and Analysis

We documented demographic information including aailed clinical history with particular reference to their personalfamily history of any type or form of psoriasis. The data on age atgnosis of IBD, clinical course, therapeutic options used tonage their IBD, use of concurrent immunomodulators, and thee of initiation of infliximab along with its frequency and dosere collected. The information on date of onset of psoriatic lesionng with its location, type, and therapeutic approaches used tonage these lesions was gathered. Any changes to their IBDnagement due to psoriatic manifestations were also noted.e summary measures were calculated for making comparisonsinst the published data.

RESULTSIn all, the medical records of 75 patients were reviewed.

venty-three (97%) patients were found eligible for the presentdy, and 2 (3%) patients receiving infliximab for juvenile rheuma-d arthritis were excluded from the analyses. The patientsluded in our study were between 9 and 24 years old, and hadeived 3 to 18 doses of infliximab. Forty-three (59%) were boys,60 (82%) were diagnosed as having CD.uction of this article is prohibited.lume 52, Number 2, February 2011

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JPGN Volume 52, Number 2, February 2011 Infliximab-induced Psoriasis in Children With IBD

wwstable andwere present on the face (ears and periauricular area) 5 [83%]) and perineum (n 1 [17%]). On the basis of the adultrature, all of the patients were offered a choice of stoppingliximab and considering alternative therapy or remaining onliximab and observing for any worsening of the psoriaticnifestations. All 6 patients chose to continue on infliximabause they were in stable IBD remission. Their psoriatic rashesre managed successfully with local moisturizers and steroidam application. At the onset of psoriatic manifestation, allatients had not received any concomitant immunomodulator>7 months (range 724 months). After 8 months of presentingth psoriatic rash, 1 patient (S.D.) developed thrombocytopenia.e was discontinued from infliximab and initiated onlimumab.

DISCUSSIONOur observations suggest that the paradoxical occurrence

IIP in children with IBD may not be uncommon. A majorityour patients had CD, and in our small sample we noted aale preponderance. Among our patients, the psoriatic mani-tations were mild and commonly involved the facial area,ich is characteristically more common in children than inlts (4,5). Because all of our patients were managedinfliximab alone for >7 months before presenting withriatic reaction, we do not have data on which to speculateether concurrent use of an immunomodulator could havedified their risk of developing this paradoxical phenomenon;wever, this is an important area that could be addressed infuture.

BLE 1. Characteristics of infliximab-induced psoriasis in childr

tient Sex Diagnosis

Age at time of, y

IBD Infliximab PsoriasisDos

mg kg

T.P.) M CD 11 13 16.4 7M.H.) F CD 11 16 17 5S.D.) F CD 13 14 14.9 5L.G.) F UC 14 15 20.6 7E.E.) M CD 14 15 16.2 5L.M.) F CD 13 14 16.9 5

DCrohn disease; IBD inflammatory bowel disease; UC ulcerative coright 2011 by ESPGHAN and NASPGHAN. Unau

Our observations regarding the trends for age at psoriasis,sons for initiation of infliximab therapy, and duration ofosure to infliximab concur with that of Sherlock et al (6),o recently described IIP in 11 children with CD. Although IIPmost of their patients was managed with local therapy, 2 patientsre discontinued from infliximab and initiated on adalimumab.wever, the number of doses of infliximab, the locations ofriatic eruptions, and reasons for discontinuing infliximab in 2ients were not described in their report.

Ko et al (7) reviewed 127 reported cases of antiTNF-ants (including infliximab, adalimumab, certolizumab pegol, andnercept) related to psoriasis described between 1990 and 2007. Ajority of these patients were adults and were being treated forumatoid arthritis. Only 13% (17 patients) were treated for CD.re than half of these patients received infliximab. About 82%5 patients) presented with new-onset pustular palmoplantar typepsoriasis (7). In another review, Fiorino et al (8) described IIP in

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w.jpgn.orgadults with IBD. A majority of the patients in this reviewveloped IIP between the third and fourth dose of infliximabministration, and the average time at the onset of psoriatic rashs 14.3 weeks (8). In contrast to IIP in children, a majority ofults developed pustular palmoplantar psoriasis, and in all of thees, the biological therapy was interrupted after diagnosispsoriasis.

The exact mechanism of these psoriatic manifestations ising actively elucidated. Evolving evidence from the murinedels and human studies suggest that antiTNF-a blockers tendstimulate peripheral dendritic cells to release type 1 interferonsN) (a/b). The IFN-a induces expression of CXC ligand 9 andC ligand 10, and their common receptor CXC chemokineeptor 3 on activated T cells (CXCR3 T cells). A local typeFN expression in epidermis and dermis leads to expression ofA protein, which recruits CXCR3 T cells resulting in a Tlper 1biased immune response and development of cytotoxicn reactions (9,10).

Given that only a small proportion of patients receivingliximab therapy developed psoriatic manifestation, genetics indition to other unknown factors could be playing an importante in their susceptibility. The inherent limitations of our studysign preclude us from identifying all of the determinants of IIP inildren with IBD. Analyses of data from ongoing prospectivenical trials could prove useful in better understanding thiserging challenge.

CONCLUSIONSThere are limited data on IIP in children with IBD. It is

with IBD

Infliximab Psoriasis

,ose1

Frequency,wk Doses

Exposure,mo Location Type

8 17 40 Facial Plaque8 14 12 Facial Papular8 6 9 Facial Papular6 15 66 Perineum Papular7 12 14 Facial Scaly10 15 27 Facial Scaly

.thorized reproduction of this article is prohibited.

portant to educate children with IBD who may need infliximabtheir caretakers about this paradoxical phenomenon to mini-

ze anxiety and ensure continued care. It may be useful to includeiodic dermatological evaluation as a component of care foriatric patients with IBD on infliximab.

Acknowledgment: We acknowledge Mary Williamson, RN,N, CPN, for help in gathering important data for this manuscript.

REFERENCESMalaty HM, Fan X, Opekun AR, et al. Rising incidence of inflammatorybowel disease among children: a 12-year study. J Pediatr GastroenterolNutr 2010;50:2731.

Saeed SA, Crandall WV. Managing Crohn disease in children andadolescents: focus on tumor necrosis factor antagonists. Paediatr Drugs2008;10:318.

Kerbleski JF, Gottlieb AB. Dermatological complications and safety ofanti-TNF treatments. Gut 2009;58:10339.

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4. Nanda A, Kaur S, Kaur I, et al. Childhood psoriasis: an epidemiologicsurvey of 112 patients. Pediatr Dermatol 1990;7:1921.

5. Nyfors A, Lemholt K. Psoriasis in children. A short review and a surveyof 245 cases. Br J Dermatol 1975;92:43742.

6. Sherlock M, Frost K, Zachos M, et al. Infliximab-induced psoriasisin pediatric Crohn disease: experience of this paradoxical eventat a tertiary centre. Can J Gastroenterol 2009;23(Suppl A):Abstr176.

7. Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation ofpsoriasis with TNF-blockade therapy: a review and analysis of 127cases. J Dermatolog Treat 2009;20:1008.

8. Fiorino G, Allez M, Malesci A, et al. Review article: Anti TNF-alphainduced psoriasis in patients with inflammatory bowel disease. AlimentPharmacol Ther 2009;29:9217.

9. Seneschal J, Milpied B, Vergier B, et al. Cytokine imbalance withincreased production of interferon-alpha in psoriasiform eruptionsassociated with antitumour necrosis factor-alpha treatments. Br JDermatol 2009;161:10818.

10. Lee HH, Song IH, Friedrich M, et al. Cutaneous side-effects in patientswith rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol 2007;156:48691.

Hiremath et al JPGN Volume 52, Number 2, February 2011

23right 2011 by ESPGHAN and NASPGHAN. Unau

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www.jpgn.org

Infliximab-induced Psoriasis in Children With Inflammatory BowelDiseaseMATERIALS AND METHODSStudy Design and SubjectsData Collection and Analysis

RESULTSDISCUSSIONCONCLUSIONSAcknowledgment