240
Psoriasiform and eczematiform lesions appear to be reactions to the class of
drugs rather than to the individual anti-TNF agent as these reactions have been
reported with infliximab, adalimumab, and certolizumab pegol [ 25 , 29 , 31 , 33 , 39 ].
When analyzing more than 13 million reports from the Food and Drug Administration
(FDA) Adverse Event Reporting System between 2004 and 2011, Kip and col-
leagues noted a total of 5432 cases of anti-TNF-related psoriasis (infliximab = 1789;
adalimumab = 3475; certolizumab pegol = 168) [ 29 ]. The control drugs they
selected in their analysis were propranolol and lithium, due to their recognized risk
of psoriasis, and mesalamine [ 29 ]. Compared to control, the proportional reporting
ratios of psoriasis for infliximab, adalimumab, and certolizumab pegol were 6.61,
12.13, and 5.43, respectively (p < 0.0001) [ 29 ]. As a class, the proportional report-
ing ratio of psoriasis for these TNF antagonists was 9.24 (p < 0.0001) [ 29 ].
Other reports have also demonstrated an association between various anti-TNF
agents and inflammatory skin lesions [ 25 , 39 ]. Of the 1004 IBD patients who were
exposed to anti-TNF therapy, Afzali et al. identified 27 patients who developed pso-
riasiform lesions (infliximab = 8, adalimumab = 10, and certolizumab pegol = 9)
[ 39 ]. In the Rahier study described previously, 62 patients had psoriasiform lesions
(infliximab = 45, adalimumab = 15, certolizumab pegol = 2) and 23 patients had
eczematiform lesions (infliximab = 15, adalimumab = 5, certolizumab pegol = 3)
[ 25 ]. Adverse inflammatory skin lesions are likely seen more commonly with inflix-
imab and adalimumab because of their increased market share compared to certoli-
zumab pegol [ 25 ].
It remains unclear whether there is a dose-dependent risk between TNF antago-
nist and the development of dermatologic adverse events. Among 71 IBD patients
who were receiving stable maintenance infliximab therapy, 9 (12.7%) were noted to
have dermatologic adverse events (psoriasis = 2, non-psoriatic skin eruptions = 7)
[ 40 ]. The median infliximab trough level in patients with dermatologic adverse
events was higher compared to those without skin adverse events (13.3 μg/mL [IQR
8.8–17.4 μg/mL] versus 6.6 μg/mL [IQR 3.2–12.7 μg/mL]), respectively, (p = 0.058)
[ 40 ]. However, in another retrospective cohort study where 264/917 (26%) of IBD
patients on maintenance anti-TNF therapy developed dermatologic adverse reac-
tions, trough infliximab levels were similar in patients with (4.2 μg/mL [IQR 2.6–
5.8 μg/mL] and without lesions (4.0 μg/mL [IQR 1.6–5.9 μg/mL] [ 41 ].
Pathophysiology
Paradoxical de novo formation or worsening of psoriasiform lesions that occur dur-
ing anti-TNF therapy is thought to be due to dysregulated interferon-α (IFN-α) pro-
duction via plasmacytoid dendritic cell precursors (PDCs) [ 42 , 43 ]. While there are
certain genetic predispositions that are linked to classic psoriasis, including
HLA-Cw6, HERV-K, as well as LCE3C and LCE3B deletions, it remains unclear
which genetic pathways are responsible for anti-TNF-related psoriasiform skin
lesions [ 44 , 45 ]. In homeostatic conditions, TNF-α and IFN-α behave as opposite
U. Wong and R.K. Cross