Psoriasis was managed successfully with topical steroid treatment in 15 of 18 (83.3%) patients. Two patients (numbers 1 and 14) had more severe skin lesions. Patient 1, treated for severe perianal fistulizing and coexistent luminal inflammatory disease with combination IFX and azathioprine maintenance therapy, abruptly lost response related to formation of IFX antibodies. His chronic psoriasis resolved off IFX with initiation of oral prednisone. Patient number 14 developed particularly severe scalp psoriasis leading to hair loss despite topical treatments, as well as psoriasis of the palms and soles. The severity of her psoriasis necessitated discontinuation of anti-TNF therapy despite an otherwise beneficial effect. Patient number 2 refused chronic topical steroid treatment and requested discontinuation of IFX because of psoriasis on the dorsum of the hands. Lesions disappeared but recurred 18 months later, when IFX was reintroduced as treatment for his chronically active CD.
DNA was available on 234 subjects with IBD (147 with CD, 87 with UC). Treatment with IFX was initiated in 35 of 147 (23.8%) patients with CD. Psoriasis developed in 10 of 35 IFX-exposed patients with CD. There was no association between any of the interrogated SNPs and IFX exposure status (data not shown); however, 3 of the 5 polymorphisms tested (rs10489628, rs10789229, and rs1343151) were significantly more prevalent among patients developing psoriasis following IFX therapy in comparison with patients with CD treated with IFX, but who did not develop psoriasis. Of note, despite similar allele frequencies, only 1 of these 3 polymorphisms (rs10489628) was able to clearly distinguish subjects with CD from subjects with UC. The effects demonstrated were independent in an additive fashion, with the simultaneous homozygous carriage of both rs10489628 and rs10789229 having the highest risk of IFX-induced psoriasis (odds ratio 17.5, P = 0.02, 95% CI 1.6–196.3). Interestingly, neither of the variants previously recognized to have an independent association with psoriasis de novo (rs2201841 and rs11209026) demonstrated any association with IFX-induced psoriasis. More important, we were unable to demonstrate an association between SNP rs11209026 (R381Q), the IL-23R SNP that has the strongest independent association with both CD and psoriasis susceptibility, and the development of IFX-induced psoriasis; all (35/35) subjects were homozygous for the common (G) allele of rs11209026. Numerically, more patients with UC than CD carried the protective “A” allele for this SNP (6% vs 1.5%, NS). Results of IL-23R SNP analyses are summarized in Table 3.
Psoriasis is a chronic skin disorder affecting approximately 2% of the population. Family history is often positive in affected patients (35,36). Psoriasis, either new-onset or worsening of existing lesions, has been described in association with all presently licensed TNF-α antagonists: IFX, adalimumab, etanercept, and more recently certolizumab pegol (10–12,37,38). This paradoxical reaction is not limited to patients with IBD, but it has also been described in rheumatological conditions, including rheumatoid arthritis and seronegative spondyloarthropathies (10). The association between IBD and psoriasis is not surprising considering both conditions are associated with immune dysregulation, and TNF-α has been implicated in the pathogenesis of both CD and psoriasis (39,40). The apparent paradox lies with the development of new-onset psoriasis or worsening of existing psoriasis in the setting of TNF-α antagonist therapy because these medications are used effectively in psoriasis treatment regimens.
Reported patients with anti-TNF-α–induced psoriasis or psoriasiform eruptions are almost all adults (12). Cullen et al (14) recently presented a review of 120 cases of anti-TNF-α–induced psoriasis in patients with IBD previously reported in the literature, with the addition of a further 30 new cases. In a cohort of adalimumab-treated pediatric patients with CD, Viola et al (18) reported that 1 of 23 patients treated developed psoriasis. Hiremath et al (19) described a series of 6 pediatric patients with IBD who developed psoriasis following IFX therapy. To date there have been only a small number of published case reports and series in pediatric patients with IBD (15–17,20).
We found a prevalence of new-onset psoriasis or psoriasiform lesions of 10.5% among our IFX-treated pediatric CD population. Given the paucity of published pediatric case reports and the high prevalence in our cohort, it is likely that this adverse event is underreported in the medical literature. In a cohort of >700 IFX-treated adult patients with CD, a variety of skin eruptions, including psoriasiform lesions, occurred in 20% of patients. Almost 10% of the entire cohort, with lesions severe enough to warrant dermatology referral, was confirmed to have psoriasiform exanthemata (41). It is likely that the baseline prevalence of psoriasis among adult patients with CD without anti-TNF treatment is higher than that among children. Psoriasis prevalence rates of 10% to 11% in mainly adult patients with CD have been described (21,22); data on the prevalence of coexistent psoriasis in pediatric IBD populations are lacking. We have not formally explored the background psoriasis prevalence rate in patients not exposed to TNF-α antagonist therapy and we recognize this as a study limitation. Nonetheless, given the myriad of case reports and case series now available, this adverse event seems to be a true increase in prevalence in TNF-α–treated patients, and the Food and Drug Administration now recommends that manufacturers of TNF-α antagonist products record this on the product-prescribing information. Our experience confirms this warning to apply to children, perhaps particularly those with a positive family history of psoriasis, who in our series developed the more disturbing skin lesions.
We did not perform a skin biopsy in any of our affected patients because the clinical characteristics appeared consistent with psoriasis, and the diagnosis was confirmed in all cases by a pediatric dermatologist. Some authors have suggested that these skin eruptions are different from classic psoriasis seen in the absence of TNF-α antagonist exposure and prefer to use the term “psoriasiform” when describing the skin manifestations. Seneschal et al studied skin biopsy specimens from 11 patients who developed psoriasiform lesions following TNF-α antagonist therapy for various rheumatologic disorders. Although the lesions visually appeared similar to those of psoriasis, histologic features varied, with spongiosus present on several specimens. Other differences included increased type 1 interferon (IFN) expression and increased expression of the chemokine receptor CXCR3 in the eruptions occurring in the setting of anti-TNF-α treatment (42).
The majority of patients reported in this case series continued IFX therapy because their skin eruptions were successfully treated with topical therapy. This is consistent with outcomes reported by Fidder et al (41), and in contrast to the findings of Rahier et al and Cullen et al (13,14), who report that up to 40% of patients with IBD developing new-onset or worsening of existing psoriasiform skin lesions discontinue anti-TNF therapy as a consequence of the adverse event.
The onset of psoriasis following TNF-α antagonists does not appear to be drug specific, and there is a risk of recurrence following instigation of an alternate anti-TNF-α agent (43). Although the majority of reported cases have been in association with IFX use, this phenomenon likely results from the earlier licensing, and hence more extensive usage, of this product. It is likely that we will see more reports of psoriasis and psoriasiform lesions with increased use of other classes of TNF-α antagonists and with the introduction of newer products.
The pathogenesis of this paradoxical process is not yet fully understood. We explored polymorphisms in the IL-23R gene, which is implicated in both CD and psoriasis susceptibility. IL-23 is a key proinflammatory cytokine, driving the local TH17 effector response. The binding of IL-23 to the receptor IL-23R leads to the phosphorylation of STAT3 and the subsequent expression of various IL-23–dependent genes, including IL-17A. The IL-23/TH17 axis has received considerable interest in the last few years because it is key in protective immunity against infections and pathogenic in autoimmune-type diseases such as psoriasis and CD. In such cases, tissue-derived IL-23 drives pathologic TH17 effector responses, leading to overwhelming inflammation. Genetic studies have shown that the less common A allele of the SNP rs11209026 within IL-23R confers approximately 3-fold protection against developing CD (30) and 2-fold protection against psoriasis (32). This SNP results in an arginine (R) to glutamine (Q) substitution at position 381 (R381Q) within the cytoplasmic domain of the IL-23R. Although the genetic association has been replicated numerous times, the functional consequences of carrying the protective gene variant have only recently been elucidated by Di Meglio et al. Their studies demonstrated that the R381Q protective variant negatively affects IL-23 signal transduction, reducing STAT3 phosphorylation and ultimately decreasing the amount of IL-17A produced in response to IL-23 stimulation (44); however, the frequency of this variant in the general population is low, Indeed, none of the subjects in our genetic substudy who received IFX carried this allele. Nevertheless, the findings of Di Meglio et al support the concept that IL-23 plays a major role in local tissue, rather than systemic, inflammation, and specifically that it does this by mediating the local TH17 effector response. Although R381Q is the only variant for which the precise mechanism of effect has been elucidated, multiple independent IL-23R polymorphisms have now been reported to be associated with both CD and psoriasis, suggesting a model of allelic heterogeneity where disruption of IL-23R function can occur from several distinct genetic insults. Our data were consistent with this; although the common variant for R381Q was pervasive throughout all subjects, variation within 3 of the 4 other SNPs clearly modulated a patient's risk of IFX-induced psoriasis; however, only 1 of those 3 SNPs differentiated study patients with CD from those with UC, and none of them have been previously recognized to increase the risk of psoriasis de novo. The only SNP within the study with a previously demonstrated association with psoriasis de novo had no significant association with IFX-induced psoriasis, nor did it vary between subjects with CD versus UC. The IL-23R is a relatively large gene. Understanding the complex, pleiotropic action of IL-23R and the specific variants that give rise to various autoimmune traits will undoubtedly increase progress in our understanding of the molecular pathophysiology underlying these chronic autoinflammatory conditions.
Although the exact pathogenic mechanism whereby IFX induces psoriasis has yet to be elucidated, there is evidence supporting a role for increased IFN-α expression as a result of TNF-α blockade. IFN-α has been implicated in the pathogenesis of psoriasis (46). It is produced by plasmocytoid predendritic cells, which are found in increased numbers in psoriatic skin lesions. IFN-α is required for the activation of T cells in psoriatic skin lesions in an in vivo mouse model (47). TNF-α inhibits the production on INF-α by inhibiting the generation of plasmocytoid predendritic cells in vitro; it therefore seems intuitive that blocking TNF-α will lead to an increased production of INF-α (48), with the potential for psoriasis development. Our study's findings suggest that this mechanism may be further modulated in susceptible subjects via the local action of IL-23.
This case series highlights an important adverse event seen in association with IFX usage and the need for continued vigilance in all patients treated with TNF-α antagonists. We suggest early referral to a dermatologist for diagnosis and early instigation of treatment for all children with skin eruptions suggestive of psoriasis or psoriasiform eruptions while being treated with anti-TNF-α therapy. Most children respond well to topical therapy without the need to discontinue IFX therapy. We found a significant association between polymorphisms in the IL-23R gene and the subsequent development of psoriasis/psoriasiform lesions, and it is possible that variants in the IL-23 axis play a role in the development of this paradoxical adverse event; however, our sample size is small and therefore not adequately powered to draw any firm conclusion. In addition, DNA samples were not available on all patients described. We recognize these as study limitations. Nonetheless, we believe that our findings are hypothesis generating and warrant further exploration in large, adequately powered studies. Until further information regarding the pathogenesis of psoriasis and psoriasiform lesions in patients receiving TNF-α antagonists, it is not yet possible to identify those at highest risk and all patients should be monitored regularly for this unexpected adverse event.
The authors acknowledge colleagues at the Centre for Applied Genomics at The Children's Hospital of Philadelphia for performing analysis of IL-23 receptor polymorphisms.
1. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology
2. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab therapy in children with chronically active severe Crohn's disease. Inflamm Bowel Dis
3. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet
4. Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord
5. van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum
6. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum
7. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet
8. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol
9. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet
10. Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum
11. Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog Treat
12. Wollina U, Hansel G, Koch A, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol
13. Rahier JF, Buche S, Peyrin-Biroulet L, et al. Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti-tumor necrosis factor therapy. Clin Gastroenterol Hepatol
14. Cullen G, Kroshinsky D, Cheifetz AS, et al. Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature. Aliment Pharmacol Ther
15. Costa-Romero M, Coto-Segura P, Suarez-Saavedra S, et al. Guttate psoriasis induced by infliximab in a child with Crohn's disease. Inflamm Bowel Dis
16. Avila Alvarez A, Garcia-Alonso L, Solar Boga A, et al. [Flexural psoriasis induced by infliximab and adalimumab in a patient with Crohn's disease]. An Pediatr (Barc)
17. Pourciau C, Shwayder T. Occurrence of pustular psoriasis after treatment of Crohn disease with infliximab. Pediatr Dermatol
18. Viola F, Civitelli F, Di Nardo G, et al. Efficacy of adalimumab in moderate-to-severe pediatric Crohn's disease. Am J Gastroenterol
19. Hiremath G, Duffy L, Leibowitz I. Infliximab-induced psoriasis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr
20. Perman MJ, Lovell DJ, Denson LA, et al. Five cases of anti-tumor necrosis factor alpha-induced psoriasis presenting with severe scalp involvement in children. Pediatr Dermatol
21. Yates VM, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohn's disease and ulcerative colitis. Br J Dermatol
22. Lee FI, Bellary SV, Francis C. Increased occurrence of psoriasis in patients with Crohn's disease and their relatives. Am J Gastroenterol
23. Cohen AD, Dreiher J, Birkenfeld S. Psoriasis associated with ulcerative colitis and Crohn's disease. J Eur Acad Dermatol Venereol
24. Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn's disease. J Am Acad Dermatol
25. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet
26. Duffin KC, Krueger GG. Genetic variations in cytokines and cytokine receptors associated with psoriasis found by genome-wide association. J Invest Dermatol
27. Elder JT. Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun
28. Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet
29. Franke A, Balschun T, Karlsen TH, et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet
30. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science
31. Nair RP, Ruether A, Stuart PE, et al. Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J Invest Dermatol
32. Capon F, Di Meglio P, Szaub J, et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet
33. Einarsdottir E, Koskinen LL, Dukes E, et al. IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease. BMC Med Genet
34. Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet
35. Morris A, Rogers M, Fischer G, et al. Childhood psoriasis: a clinical review of 1262 cases. Pediatr Dermatol
36. Augustin M, Glaeske G, Radtke MA, et al. Epidemiology and comorbidity of psoriasis in children. Br J Dermatol
37. Klein RQ, Spivack J, Choate KA. Psoriatic skin lesions induced by certolizumab pegol. Arch Dermatol
38. Mocciaro F, Renna S, Orlando A, et al. Severe cutaneous psoriasis after certolizumab pegol treatment: report of a case. Am J Gastroenterol
39. Kupper TS. Immunologic targets in psoriasis. N Engl J Med
40. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med
41. Fidder H, Schnitzler F, Ferrante M, et al. Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut
42. Seneschal J, Milpied B, Vergier B, et al. Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments. Br J Dermatol
43. Cohen JD, Bournerias I, Buffard V, et al. Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series. J Rheumatol
44. Di Meglio P, Di Cesare A, Laggner U, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PloS One
45. Cleynen I, Henckaerts L, Claes K, et al. Development of psoriasiform skin lesions under anti-TNF therapy: a common link with IL23R gene variants? Gastroenterology
46. Eriksen KW, Lovato P, Skov L, et al. Increased sensitivity to interferon-alpha in psoriatic T cells. J Invest Dermatol
47. Nestle FO, Conrad C, Tun-Kyi A, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med
48. Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA