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Original Research |

Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort StudySkin Lesions Associated With Anti-TNF Therapy in Patients With IBD

Isabelle Cleynen, PhD; Wouter Van Moerkercke, MD; Thomas Billiet, MD; Pieter Vandecandelaere, MD; Niels Vande Casteele, PhD; Christine Breynaert, MD, PhD; Vera Ballet; Marc Ferrante, MD, PhD; Maja Noman, MD; Gert Van Assche, MD, PhD; Paul Rutgeerts, MD, PhD; Joost J. van den Oord, MD, PhD; Ann Gils, PharmD, PhD; Siegfried Segaert, MD, PhD*; and Séverine Vermeire, MD, PhD*
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 8 December 2015.

* Drs. Segaert and Vermeire contributed equally to this work.


From KU Leuven and University Hospitals Leuven, Leuven; AZ Groeninge, Kortrijk; and AZ Delta, Roeselare, Belgium.

Acknowledgment: The authors thank Nooshin Ardeshir Davani, Karolien Claes, Griet Compernolle, Tamara Coopmans, Sophie Organe, Sophie Tops, and Willem-Jan Wollants for their excellent technical support and João Guadelha Sabino, MD, and Kostas Papamichael, MD, for help with data collection.

Financial Support: By the Research Foundation Flanders (FWO), Belgium; the Geconcerteerde Onderzoekacties of KU Leuven (grant GOA/11/015); and an unrestricted grant from Janssen Biologics. Drs. Cleynen and Vande Casteele (postdoctoral fellows) and Drs. Vermeire, Van Assche, and Ferrante (clinical researchers) are funded by the Research Foundation Flanders, Belgium.

Disclosures: Dr. Cleynen reports grants from the Geconcerteerde Onderzoekacties of KU Leuven and Janssen Biologics during the conduct of the study. Dr. Vande Casteele reports grants from the Research Foundation Flanders (FWO), Belgium, and personal fees from Merck Sharpe & Dohme (MSD), Janssen Biologics, Pfizer, AbbVie, and UCB outside the submitted work. Dr. Ferrante reports grants from Takeda Pharmaceutical Company during the conduct of the study; personal fees and nonfinancial support from AbbVie, MSD, Janssen Pharmaceutica, and Zeria Pharmaceutical during the conduct of the study; personal fees from Ferring Pharmaceuticals, Chiesi Farmaceutici, Tillotts Pharma, and Boehringer Ingelheim outside the submitted work; and nonfinancial support from Tillotts Pharma and Boehringer Ingelheim outside the submitted work. Dr. Van Assche reports consultancies with Zealand Pharma, Shire, Abbott, Novartis, MSD, Janssen Pharmaceutica, Bristol-Myers Squibb, Ferring Pharmaceuticals, Chiesi Farmaceutici, and Takeda Pharmaceutical Company; grants from MSD, Abbott, and Zealand Pharma outside the submitted work; and payment for lectures from Janssen Pharmaceutica, Abbott, Ferring Pharmaceuticals, Aptalis, and MSD. Dr. Rutgeerts reports grants from Merck, AbbVie, and UCB and personal fees from Merck, AbbVie, UCB, Johnson & Johnson, Millennium Pharmaceuticals, Tillotts Pharma, MedImmune, Pfizer, Robarts Research Institute, Dr Falk Pharma, and Neovacs outside the submitted work. Dr. Gils reports grants from Pfizer; personal fees from Pfizer, AbbVie, MSD, and Janssen Biologics; and other from apDia outside the submitted work. Dr. Vermeire reports grants from AbbVie, Takeda Pharmaceutical Company, and MSD during the conduct of the study and consultancy or speakers fees paid to her institution by AbbVie, Takeda Pharmaceutical Company, MSD, Pfizer, Genentech, Galapagos, Hospira, Mundipharma, Johnson & Johnson, Shire, Ferring Pharmaceuticals, and Celgene during the conduct of the study and outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0729.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Cleynen (e-mail, isabelle.cleynen@med.kuleuven.be).

Requests for Single Reprints: Séverine Vermeire, MD, PhD, Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, Box 701, 3000 Leuven, Belgium; e-mail, severine.vermeire@uzleuven.be.

Current Author Addresses: Drs. Cleynen and Billiet: Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Dr. Van Moerkercke: AZ Groeninge, President Kennedylaan 4, 8500 Kortrijk, Belgium.

Dr. Vandecandelaere: AZ Delta, Rode Kruisstraat 20, 8800 Roeselare, Belgium.

Drs. Vande Casteele and Gils: Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Dr. Breynaert: Department of General Internal Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.

Ms. Ballet and Dr. Noman: Department of Gastroenterology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.

Drs. Ferrante, Van Assche, Rutgeerts, and Vermeire: Department of Gastroenterology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Dr. van den Oord: Department of Pathology, Lab Translational Cell & Tissue Pathology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Dr. Segaert: Dermatology, University Hospitals Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.

Author Contributions: Conception and design: I. Cleynen, M. Ferrante, P. Rutgeerts, S. Segaert, S. Vermeire.

Analysis and interpretation of the data: I. Cleynen, N. Vande Casteele, C. Breynaert, G. Van Assche, P. Rutgeerts, J.J. van den Oord, S. Segaert, S. Vermeire.

Drafting of the article: I. Cleynen, P. Rutgeerts, S. Vermeire.

Critical revision of the article for important intellectual content: M. Ferrante, G. Van Assche, P. Rutgeerts, J.J. van den Oord, S. Segaert, S. Vermeire.

Final approval of the article: I. Cleynen, W. Van Moerkercke, T. Billiet, P. Vandecandelaere, N. Vande Casteele, C. Breynaert, V. Ballet, M. Ferrante, M. Noman, G. Van Assche, P. Rutgeerts, J.J. van den Oord, A. Gils, S. Segaert, S. Vermeire.

Provision of study materials or patients: W. Van Moerkercke, V. Ballet, M. Ferrante, P. Rutgeerts, S. Segaert, S. Vermeire.

Statistical expertise: I. Cleynen, S. Vermeire.

Obtaining of funding: S. Vermeire.

Administrative, technical, or logistic support: M. Noman, A. Gils, S. Vermeire.

Collection and assembly of data: I. Cleynen, W. Van Moerkercke, T. Billiet, P. Vandecandelaere, C. Breynaert, V. Ballet, M. Ferrante, G. Van Assche, P. Rutgeerts, J.J. van den Oord, A. Gils, S. Segaert, S. Vermeire.


Ann Intern Med. 2016;164(1):10-22. doi:10.7326/M15-0729
Text Size: A A A

Background: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti–tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized.

Objective: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions.

Design: Retrospective cohort.

Setting: Single IBD tertiary referral center.

Patients: 917 consecutive patients with IBD who initiated anti-TNF therapy.

Measurements: Skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers.

Results: During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions.

Limitation: Retrospective nature and no matched control group of patients not receiving anti-TNF therapy.

Conclusion: Skin lesions occur frequently in association with anti-TNF therapy but rarely require discontinuation of therapy. Close surveillance and early referral to a dedicated dermatologist are recommended.

Primary Funding Source: Research Foundation Flanders (FWO), Belgium; Geconcerteerde Onderzoekacties of KU Leuven; and Janssen Biologics.

Figures

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Appendix Figure 1.

Hematoxylin and eosin staining of psoriasis (top), psoriasiform eczema (middle), and eczema (bottom).

All histologic pictures are original magnification × 50. Top. A skin lesion showing irregular acanthosis, focal parakeratosis, and crust/scale formation, resembling psoriasiform eczema. Middle. A skin lesion showing regular elongation and clubbing of rete ridges, thinning of suprapapillary epidermis, confluent parakeratosis, and superficial perivascular inflammation, resembling psoriasis. Bottom. A skin lesion showing irregular and plump acanthosis, multifocal parakeratosis and spongiosis, and superficial perivascular inflammation, resembling spongiotic eczema.

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Appendix Figure 2.

Histograms showing the distribution of the genetic risk sums in patients with (top) and without (bottom) skin lesions.

The genetic risk sum for each patient is the sum for variants that are more prevalent in patients with skin lesions than in those without them: LCE3B/LCE3D (rs6677595), PRR5L (rs12295535), ZC3H12C (rs4561177), and TYK2 (rs12720356) (Appendix Table 2). For this analysis, 847 patients were included. Thirteen were excluded because no DNA was available, and 57 failed quality control, which was performed as described elsewhere (32, 41). The figure was generated using Stata (StataCorp).

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Figure 1.

Typical characteristics and locations of psoriasiform eczema skin lesions.

The condition is characterized by orange-red, ill-defined macules, papules, or plaques that often affect the flexural regions, such as the retroauricular (A), umbilicus (B), axillar (C and D), and intermammary or submammary (E) regions. Lesions can also be located elsewhere, such as on the buttocks (F). This type of lesion can easily be confused with psoriasis because it shares the typical orange-red color, but it often lacks the silvery-white scales and the sharp borders of psoriasis. Unlike psoriasis, psoriasiform eczema is frequently superinfected with Staphylococcus aureus, leaving oozing or crusted lesions (A).

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Figure 2.

Eczema of the penis and scrotum (left) and the knee folds (right).

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Figure 3.

Palmoplantar pustulosis with superficial pustules on inflamed skin, typically located at the concavity of the feet.

The inset in the upper right corner is a close-up of the left foot.

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Figure 4.

Psoriasis with sharply demarcated infiltrated erythematosquamous lesions on the arm (left) and scalp (right).

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Figure 5.

Patient with typical cutaneous lesions while receiving infliximab.

Panels A to C show palmoplantar pustulosis (panel B is a close-up of the hand). Panels D to F show psoriasiform eczema with orange-red, ill-defined erythematosquamous lesions. Panel F is a close-up of the right thigh showing psoriasiform dermatitis surrounded by bacterial folliculitis caused by Staphylococcus aureus.

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Figure 6.

Nail deformities in a patient with alopecia universalis that developed while the patient was treated with infliximab.

The patient also had nail deformities associated with alopecia areata (trachyonychia, or sandpaper nails). All fingernails were affected (A and B). The sharp demarcation between normal and diseased toenails indicates the time at which the alopecia areata arose (C and inset).

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Figure 7.

Psoriasiform dermatitis of the intergluteal region (A) and the genitalia (C).

Bacterial cultures were positive for Staphylococcus aureus and Streptococcus pyogenes group G. The lesions were treated with oral flucloxacillin and topical silver sulfadiazine cream in the morning and a combination cream containing betamethasone valerate and fusidic acid in the evening. A positive evolution of the lesions was noted after 9 days of treatment (B and D).

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Summary for Patients

Rashes in Patients With Ulcerative Colitis or Crohn Disease Being Treated With Drugs That Block Tumor Necrosis Factor

The full report is titled “Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study.” It is in the 5 January 2016 issue of Annals of Internal Medicine (volume 164, pages 10-22). The authors are I. Cleynen, W. Van Moerkercke, T. Billiet, P. Vandecandelaere, N. Vande Casteele, C. Breynaert, V. Ballet, M. Ferrante, M. Noman, G. Van Assche, P. Rutgeerts, J.J. van den Oord, A. Gils, S. Segaert, and S. Vermeire.

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