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Journal of Crohn's and Colitis (2012) 6, 518–523

Induction of psoriasis with anti-TNF agents in patientswith inflammatory bowel disease: A report of 21 cases☆

Iván Guerra a,⁎, Alicia Algaba a, José Lázaro Pérez-Calle b, María Chaparro c,Ignacio Marín-Jiménez d, Raquel García-Castellanos e, Yago González-Lama f,Antonio López-Sanromán g, Noemí Manceñido h, Pilar Martínez-Montiel i,Elvira Quintanilla j, Carlos Taxonera k, Mónica Villafruela l,Alberto Romero-Maté m, Pilar López-Serrano b,Javier P. Gisbert c, Fernando Bermejo a

a Digestive Diseases Department, Hospital de Fuenlabrada, Spainb Digestive Diseases Department, Fundación Hospital de Alcorcón, Spainc Digestive Diseases Department, Hospital La Princesa, Instituto de Investigación Sanitaria Princesa (IP) and Centro de inves-tigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spaind Digestive Diseases Department, Hospital Gregorio Marañón, Spaine Digestive Diseases Department, Fundación Jiménez Díaz, Spainf Digestive Diseases Department, Hospital Puerta de Hierro, Spaing Digestive Diseases Department, Hospital Ramón y Cajal, Spainh Digestive Diseases Department, Hospital Infanta Sofía, Spaini Digestive Diseases Department, Hospital Doce de Octubre, Spainj Digestive Diseases Department, Hospital Severo Ochoa, Spaink Digestive Diseases Department, Hospital Clínico San Carlos, Spainl Digestive Diseases Department, Hospital Príncipe de Asturias, Spainm Dermatology Department, Hospital de Fuenlabrada, Madrid, Spain

Received 6 September 2011; received in revised form 19 October 2011; accepted 19 October 2011

Abbreviations ADA, Adalimumab; Ctumor necrosis factor; UC, ulcerative☆ Representing the Community of Ma⁎ Corresponding author at: Hospital d

916006302; fax: +34 916006100.E-mail address: ivan.guerra@salud.

1873-9946/$ - see front matter © 2011doi:10.1016/j.crohns.2011.10.007

KEYWORDSAdalimumab;Crohn's disease;Inflammatory bowel disease;Infliximab;Psoriasis;Ulcerative colitis

Abstract

Aim: Anti-tumor necrosis factor (TNF)-alpha agents are widely used for the treatment of bothinflammatory bowel disease (IBD) and psoriasis. Psoriatic skin lesions induced by anti-TNF havebeen described in patients with IBD. We report a case series of psoriasis induced by anti-TNFagents in IBD patients.Methods: Systematic analysis of cases of psoriasis induced by anti-TNF in an IBD patient cohortin tertiary hospitals of Madrid.

D, Crohn's disease; CI, confidence interval; IBD, inflammatory bowel disease; IFX, infliximab; TNF,colitis.drid Inflammatory Bowel Disease Study Group (ENICMAD by its Spanish acronym), Spain.e Fuenlabrada, Servicio de Digestivo, Camino del molino, 2. 28942, Fuenlabrada, Madrid, Spain. Tel.:+34

madrid.org (I. Guerra).

European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

519Psoriasis by anti-TNF in inflammatory bowel disease

Results: A total of 21 of 1294 patients with IBD treated with anti-TNF-alpha agents developeddrug-induced psoriasis (cumulative incidence 1.62%; 95% CI 1.06%–2.47%): 14 patients withinfliximab and 7 with adalimumab; seventeen with Crohn's disease, 4 with ulcerative colitis.The onset of skin lesions varied in a wide range of time (after a mean 13±8 doses). The most fre-quent site of skin lesions was the limbs (62%) followed by the trunk (48%) and the scalp (43%).The psoriasis phenotypes were plaque psoriasis (57%), scalp (14%), palmoplantar pustulosis(14%), pustular generalized psoriasis (5%), guttate (5%) and inverse (5%). Four patients inter-rupted the anti-TNF treatment, and that led to the complete regression of lesions in 1 ofthem. The other 17 patients were maintained on anti-TNF therapy and managed with topicalsteroids.Conclusion: Psoriatic lesions can be induced by anti-TNF drugs. Plaque psoriasis on the extrem-ities and trunk were the most frequent presentations in our series. Topical steroid treatment iseffective in most patients. Anti-TNF discontinuance may be reserved for patients with severepsoriasis or patients without response to topical therapy.© 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

1. Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatoryprocess that includes Crohn's disease (CD), ulcerative colitis(UC) and IBD type unclassified. Although its etiology is un-known, the immune mechanism plays an essential role inits chronic development and progression.1 Tumor necrosisfactor alpha (TNFα) is a cytokine with a critical role in thepathogenesis of several inflammatory diseases such as IBDor psoriasis.2 Because of this, anti-TNF agents are amongthe therapeutic options available for IBD.3 Currently, theanti-TNF agents that are most commonly used in the treat-ment of patients with IBD are infliximab (IFX) and adalimu-mab (ADA). Their use has led to a very significant advancein the treatment of not only IBD, but also in the treatmentof other chronic inflammatory diseases such as psoriasis orpsoriatic arthritis.4 Paradoxically, the onset of psoriatic le-sions has been observed in patients on anti-TNF treatmentdue to other diseases. The cause of this side effect has notbeen clearly identified yet.5 This study analyzes a case se-ries of psoriasis induced by anti-TNF treatment in a largemulticenter cohort of IBD patients in the Madrid region,Spain.

2. Methods

We retrospectively identified all cases of psoriasis observed ina multicenter cohort of patients diagnosed with IBD under IFXor ADA treatment, followed in 12 University Hospitals in theMadrid region, Spain.6 The study was approved by the EthicsCommittee of the steering center (Hospital Universitario deFuenlabrada).

In each case, psoriasis was diagnosed by the gastroenter-ologist and confirmed by a dermatologist who carried out abiopsy of the lesions only in those patients in whom it wasconsidered necessary.

Information extracted from the clinical records includeddemographic data, type of IBD, years from diagnosis, diseaselocation and behavior according to the Montreal classificationin Crohn's disease patients,7 anti-TNF treatment, concomitanttreatments, personal and family history of psoriasis, time ofonset of psoriasis, site of lesions, psoriasis phenotypes,

management after psoriasis diagnosis and response to thatmanagement.

Definition of response: we defined a complete responseas the disappearance of all psoriasis lesions; a partial responsewas defined as an improvement in lesions without completeresolution; no response was defined as the absence of im-provement with the treatment performed.

2.1. Statistical analysis

Statistical analysis (SPSS; SPSS Inc., Chicago, IL, USA) includ-ed descriptive statistical analysis. Qualitative variables wereexpressed as percentages, with confidence intervals (CI),and quantitative variables as expressed as the mean andstandard deviation or median and interquartile range, accord-ing to the presence or absence of a normal distribution. TheKolmogorov–Smirnov test was used to evaluate normality incontinuous variables.

3. Results

3.1. Patients characteristics

A total of 1294 patients with IBD, 1087 (84%) CD and 207(16%) with UC, had been treated with anti TNF-alpha agents,IFX or ADA, until January 2011. Of the 1087 patients with CD648 (59.6%) were on IFX therapy, 371 (34.1%) were on ADAand 68 (6.3%) patients were treated with both IFX and ADA,sequentially. Of the 207 patients with UC 160 (77.3%) wereon IFX therapy, 41 (19.8%) on ADA and 6 (2.9%) receivedboth drugs sequentially. Twenty-one of them developeddrug-induced psoriasis (cumulative incidence 1.62%; 95% CI1.06%–2.47%). Fourteen (67%) patients were in treatmentwith IFX and seven (33%) with ADA. The mean age in patientswith psoriasis due to TNF-alpha was 39±10 years, 15 (71%)were females and 10 (47.6%) were smokers. Seventeen pa-tients (81%) with IBD had CD and four (19%) were UC pa-tients. Clinical data of the included patients are shown inTable 1.

The median duration under anti-TNF at the onset of skin le-sions was 12 months (interquartile range 36–4). In all cases ex-cept in one patient who developed psoriasis after the third

520 I. Guerra et al.

induction dose of IFX, skin lesions ocurred during maintenancetherapy (after a mean of 13±8 doses of the anti-TNF drug).The median of follow-up since the onset of psoriasis was14 months (interquartile range 16.5–9). IFX induction therapyused a standard regimen of 3 intravenous infusions at the doseof 5 mg/kg at 0, 2 and 6 weeks; ADA induction therapy doseregimen was a 160 mg subcutaneous injection, followed by80 mg 2 weeks later. All patients on maintenance therapywith ADA received the same dose: 40 mg every other week.Two patients on IFX treatment required dose escalation, oneof them with 10 mg/kg every 8 weeks and the other one with10 mg/kg every 6 weeks. The remaining patients were treatedwith 5 mg/kg of IFX every 8 weeks.

3.2. De novo psoriasis

Eighteen patients developed de novo psoriasis (cumulativeincidence 1.39%; 95% CI 0.88%–2.19%). Three patients(14.3%) had a history of psoriasis before treatment whichreappeared with the anti-TNF therapy as plaque psoriasis.Three of these cases were managed successfully with topicalagents without discontinuance of anti-TNF. Three patients(14.3% of the total patients) who developed psoriasis during

Table 1 Characteristics of the IBD patients who developeddrug-induced psoriasis.

Disease extension (UC)Left-sided colitis 3 (75%)Pancolitis 1 (25%)

Age at diagnosis (CD)A1b17 1 (6%)A2 17–40 14 (82%)A3 N40 2 (12%)

Disease location (CD)L1Ileal 5 (29%)L2 Colic 1 (6%)L3 Ileocolic 11 (65%)L4 Upper gastrointestinal tract 0

Behavior (CD) a

B1 non-stricturing nonpenetrating 9 (53%)B2 stricturingB3 penetrating 1 (6%)

2 (12%)B1+ peri-anal disease 3(17%)B3+ peri-anal disease 2(12%)

Anti-TNF-alpha treatment indicationSteroid-dependent disease 13 (61.9%)Perianal disease 3 (14.2%)Steroid-refractory 2 (9.5%)Steroid-dependent+perianal disease 1 (4.8%)Postsurgical 1 (4.8%)Associated sacroileitis 1 (4.8%)

Concomitant treatmentThiopurines 12 (57.1%)Thiopurines and oral steroids 2 (9.5%)Aminosalicylates and oral steroids 1 (4.8%)Methotrexate 1 (4.8%)a Disease location and phenotypic behavior of CD and UC were

also established in accordance with the Montreal classification.7

Abbreviations: CD, Crohn's Disease; UC, ulcerative colitis.

ADA treatment had been treated previously with IFX withoutcutaneous side effects. ADA was discontinued only in one ofthem, while the other 2 patients were treated with topicalsteroids with complete response. No patient was on treat-ment with any of the drugs that are known to induce psoria-sis (lythium, betablockers, anti-malarial drugs, and NSAID).

3.3. Location of the lesions

The most frequent sites were the limbs (62%) followed by thetrunk (48%) and the scalp (43%). Sixty-two percent of pa-tients had more than one site of skin lesions. Psoriasis pheno-types were plaque psoriasis (57%), scalp psoriasis (14%),palmoplantar pustulosis (14%), generalized pustular psoriasis(5%), guttate (5%) and inverse (5%).

3.4. Management

Discontinuance of anti-TNF agent was the initial manage-ment in 4 (19%) patients and led to complete regression oflesions in only 1 of them, with no further recurrence of pso-riasis after reintroduction of the anti-TNF therapy. Theother 3 patients presented partial response and anti-TNFwas permanently discontinued in two of them. The other pa-tient, who had palmoplantar psoriasis, was treated with top-ical steroids and the anti-TNF was reintroduced after clinicalresponse with the reappearance of mild palmoplantar psori-asis which was successfully controlled with topical therapy.

Seventeen patients (81%) were managed with topical ste-roids alone or in combination with other topical drugs for thetreatment of psoriasis. Two of them (11.8%) were treatedwith concomitant UVA therapy. Seven patients (41.2%) pre-sented a complete response to topical therapy and 9 (52.9%)had partial response. Only one patient (5.9%) did not respondto this strategy and then the anti-TNF was discontinued withcomplete response. The duration of therapy before responsewas 1–3 weeks.

Two patients were switched between anti-TNF agents (1to infliximab and 1 to adalimumab) due to a partial re-sponse. With the second anti-TNF, both patients suffered amild recurrence of psoriasis, with a complete response totopical treatment. In 9 patients (43%), skin biopsy was con-sidered necessary by the dermatologist, with confirmationof psoriasis in all cases.

4. Discussion

Anti-TNF drugs are effective in patients with chronic inflam-matory diseases such as IBD or psoriasis. Psoriasis is a cutane-ous autoimmune disease characterized by hyperproliferationand abnormal differentiation of keratinocytesmediated by ab-normal T-cell cytokine production.8 The incidence of psoriasisis increased in IBD patients regarding general population, withan Odds Ratio of 1.8 (95% CI: 1.4–2.4) having been described inpatients with CD.9, 10 The use of anti-TNF drugs is approved inthe treatment of moderate to severe psoriasis.11 Paradoxical-ly, cases of psoriasis being induced or exacerbated by treat-ment with these drugs have been described in the literature,though the mechanism by which it is produced is not clearlydefined yet. Among the mechanisms described to explain the

521Psoriasis by anti-TNF in inflammatory bowel disease

onset of psoriatic lesions due to anti-TNF therapy are the mi-gration of T-cells to the skin induced by interferon alphaproduced by plasmacytoid dendritic cells,8, 12, 13 the activa-tion of auto-reactive T-cells5, 14 or certain infectious agentssuch as Streptococcus.5, 15, 16

This paradoxical effect of the anti-TNF treatment has beendescribed with all anti-TNF drugs and in the different diseasesin which they are employed as treatment. The lesions reap-pear after switching the anti-TNF agent in almost all cases;this fact seems to indicate the existence of a class effect ofanti-TNF agents in inducing psoriatic lesions.17, 18 The preva-lence of psoriasis during anti-TNF treatment in different clini-cal entities has been estimated at 0.6–5.3%, with an incidenceof 1.04 (95% CI: 0.97–1.54) per 1000 person-years of de novopsoriasis in patients with rheumatoid arthritis.5, 19 In IBD, aprevalence of 1.6–2% of psoriasis in patients on anti-TNFtreatment has been reported in the literature.20, 21 In our se-ries, the cumulative incidence of psoriasis was 1.62% (1.39%incidence of de novo psoriasis), which is similar to the inci-dence reported in previous series, and because of the tightfollow-up that patients on anti-TNF therapy receive, the prob-ability of missing cases is low, in our opinion.

A greater absolute frequency of psoriasis cases has beenreported with the use of IFX than with ADA in the treatment ofIBD, as has also occurred in our experience, though this is prob-ably due to the subsequent introduction of ADA in the treatmentof IBD.5 Nevertheless, a significantly higher incidence of psoria-sis has been reported in rheumatological diseases in patientstreated with ADA versus IFX or etanercept.19 On the otherhand, psoriasis caused by anti-TNF drugs has been reportedmore frequently in women (58–68%, 71% in our series), thoughthe greater incidence of autoimmune diseases in women mayskew this observation. Some authors have suggested thatthere is a genetic susceptibility, though themajority of patientsdo not have a family history.5, 20, 22, 23 In our series, only 3(14.3%) patients had a family history of a first or second-degree relative with psoriasis. The age of onset of psoriatic le-sions is highly variable in both literature and our own experi-ence: the mean age of our patients is 39 years old, althoughsome pediatric cases have been reported.24–26 The timing ofonset is highly variable, from days to months after having initi-ated the treatment with anti-TNF. An earlier onset has beenreported in IBD than in patients with rheumatological disease,and in patients with ADA.5, 20, 23, 27, 28 Our data also show awider distribution of the time of onset of lesions, which isclearly more frequent during maintenance therapy. A highANA-titer could be a predisposing factor for the developmentof skin lesions, included psoriasis, in IBD patients under anti-TNF therapy, although more data are needed.29 We did notfind any risk factor for the development of psoriatic lesionsunder anti-TNF therapy because of the limited number ofcases, but this point should be evaluated in future studies pro-spectively designed.

The onset of psoriatic lesions during anti-TNF treatmentcan follow 3 primary patterns: psoriasiform eruption withtypical histopathological features of a drug reaction, show-ing lichenoid or interface dermatitis; exacerbation of pre-existing psoriasis and de novo psoriasis.27, 30 Palmoplantarpustulosis is an infrequent variant (b20%) in sporadic psoria-sis.5, 28, 31 This variety appears to be more frequent in pa-tients who are treated with anti-TNF drugs for IBD than forother diseases.31 In our series, only 3 patients (14.3%) had

palmoplantar pustulosis that significantly differs from whathas been previously reported (40–70%) in small series. Inthe largest series published in this regard, Rahier et al. re-port that 35% of patients had palmoplantar involvement.20

It is possible that the frequency of palmoplantar involve-ment in anti-TNF-induced psoriasis is not as high as previous-ly reported, and this frequency is closer to that described insporadic psoriasis. This form of psoriasis shows variationsthat are distinct from plaque psoriasis: a clear predominancein women (90%, 67% in our series) and smokers (95%, 100% inour series). Conversely, the remaining forms of psoriasisshow a distribution of 51% of women and 25% of smokers atdiagnosis (72% women and 39% smokers in our series).32

One of the possible explanations for this preponderancemay be the different expression of TNF-α in the eccrine pal-mar sweat gland and duct among patients with this form ofpsoriasis and plaque psoriasis.33 Palmoplantar pustulosisalso has been associated with metal allergies and, histologi-cally, shows an increase in mastocytes and eosinophils that isnot seen in plaque psoriasis.5

The evaluation by a dermatologist is recommended inorder to confirm the diagnosis and to initiate the most ap-propriate treatment. Performing a biopsy helps to confirmthe diagnosis by observing the histological characteristicsof idiopathic psoriasis with an increased proliferation of ker-atinocytes, with large increases in cell turnover and an ab-normal expression of keratins in the skin.28, 34, 35

Several therapeutic options are available depending on theseverity of the lesions. Topical steroids are the treatment ofchoice when cutaneous involvement is mild. Treatment withthe anti-TNF drug should probably be maintained given thatdiscontinuance may exacerbate IBD and the majority of pa-tients respond adequately to topical treatment. The majorityof our patients were treated topically without discontinuanceof the anti-TNF drug and had a partial or complete responsewith the exception of one patient in whom the anti-TNF drugwas discontinued due to lack of a response with resolution ofpsoriatic lesions. Initial treatment with topical corticosteroidsalone or concomitantly with other topical drugs (keratolytics,vitamin D analogs) or phototherapy (narrow band ultraviolet-Btreatment or soak PUVA) appears to be a reasonable initial ap-proach.5, 31 If there is no response with this treatment, therisk-to-benefit of discontinuing the anti-TNF drug should beevaluated. If the psoriatic lesions are severe, covering morethan 5% of the body surface area, or in the case of pustulosis,discontinuing the biological agent, together with topical orsystemic treatment for psoriasis (methotrexate, retinoids,and cyclosporine) is an adequate measure.36 If the lesions, de-spite not being severe, alter the patient's daily life, temporarysuspension of the biological agent with subsequent reintroduc-tion with strict clinical monitoring may be an option.

Similar to that which has been reported in previous se-ries, changing the anti-TNF drug in 2 of our patients causedreappearance of the psoriatic lesions, though their intensitywas mild and there was a good response to treatment.

Given the ever increasing use of anti-TNF drugs in patientswith IBD, it is important to keep in mind the appearance ofpsoriatic lesions among the other side effects. In our experi-ence, this paradoxical effect occurs more frequently duringmaintenance therapy, with the appearance of plaques onthe extremities as the most frequent presentation. Thoughthe literature refers to a predominance of palmoplantar

522 I. Guerra et al.

pustulosis, this has not been seen in our study. With the ex-ception of the most severe or extensive forms, topical treat-ment of the lesions is the treatment of choice for psoriasis inthese patients and the withdrawal of the anti-TNF agent isseldom needed. In all cases, we should evaluate the potentialdamage of psoriasis versus the current benefit that anti-TNFtreatment offers in controlling IBD activity, while trying notto lose prematurely the benefit of these drugs when facedwith a paradoxical effect that can be managed in the major-ity of cases with topical treatment without discontinuing thebiological agent.

Conflicts of interest

Alicia Algaba is receiving a grant from Merck, Sharp & Dohme(MSD). María Chaparro has served as speaker and has receivedresearch funding from MSD and Abbott. Javier P. Gisbert hasserved as speaker, consultant and advisory board memberfor and has received research funding from MSD and Abbott.Fernando Bermejo has served as advisory board member forMSD and has received research funding from Abbott.

Acknowledgments

None.

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