Psoriasiform Skin Lesions in Patients With IBD
Psoriasiform Skin Lesions in Patients With IBD
In this study, we demonstrate that anti-TNF antibodies, which are approved for the treatment of psoriasis, may paradoxically cause psoriasiform skin lesions in patients with IBD. This study contributes significantly to our understanding of these lesions and differs from previous retrospective case series for a number of reasons. In contrast to previous studies, the data were collected prospectively and all patients with skin lesions were seen by the same board-certified dermatologist. This allowed for the calculation of incidence rates of these lesions. We identified smoking as the major risk factor for these lesions. In addition, this study contains a detailed histopathological analysis and provides, for the first time, evidence that Th1 and Th17 cells play a key role in the pathogenesis of these lesions, suggesting similarities in the pathogenesis of anti-TNF-induced psoriasiform skin lesions and that of psoriasis. We also provide first proof of principle that anti-IL-12/anti-IL-23 antibody therapy, which is directed against Th1 and Th17 cells, is highly effective in patients with severe anti-TNF-induced psoriatic skin lesions. In addition, we performed a detailed genotype analysis of IBD- and psoriasis-associated IL23R, IL23, IL12B gene variants in patients with anti-TNF-induced skin lesions.
Psoriasiform and eczematiform skin lesions are the most frequently observed dermatological adverse events in patients treated with anti-TNF antibody. Several case series analysing severe skin lesions in patients with IBD caused by anti-TNF inhibitors have been published. Due to the retrospective nature of the majority of previous studies, the exact prevalence of psoriasiform skin lesions in patients receiving anti-TNF antibodies is largely unknown. In our prospective study, almost 5% of all anti-TNF-treated patients developed psoriasiform skin lesions, which is consistent with data derived from anti-TNF-treated patients with rheumatoid arthritis. Rahier et al extrapolated data from a French IBD centre and suggested that the risk of developing inflammatory skin lesions (psoriasiform or eczematiform) is around 5% in anti-TNF-treated patients with IBD and the definitive need to withdraw anti-TNF treatment due to uncontrolled skin lesions is around 1%. Similarly, in our study, in 7 of 434 anti-TNF-treated patients with IBD (1.6%) anti-TNF treatment had to be stopped due to severe skin lesions. In our study, most patients with psoriasiform lesions had palmoplantar psoriasis, which was also one of the most common skin manifestations in other studies.
Similar to our study, in which 90.5% of patients with anti-TNF-induced psoriasis had CD, the majority of patients in other studies were diagnosed with CD and not UC. This is in agreement with the clinical observation that there is a stronger overlap between psoriasis and CD compared with UC, which may be related to the stronger association of CD and psoriasis with IL23R and IL12B SNPs than observed in UC. However, considering the later approval for infliximab and adalimumab for the treatment of UC (compared with CD), this may partially reflect a prescription bias of anti-TNF inhibitors in patients with IBD.
Smokers seem to be especially prone to psoriasiform skin lesions. In our study, 76.2% of the patients with psoriasiform skin lesions were active smokers or ex-smokers. In multivariate analysis, being a smoker or having a history of smoking was the strongest predictive factor for developing psoriasiform skin lesions (p=0.007; OR 4.24, 95% CI 1.55 to 13.60). In addition, we identified an increased BMI as a risk factor for developing these lesions (p=0.029; OR 1.12, 95% CI 1.01 to 1.24). Interestingly, smoking and an increased BMI have also been shown to increase the risk for psoriasis, suggesting similarities in the disease pathogenesis of anti-TNF-induced psoriasiform skin lesions and psoriasis.
We had to stop anti-TNF therapy in 7 of 21 patients with skin lesions (33.3%) due to the severity of lesions and the lack of efficacy of topical therapy. In the study by Rahier et al, 40% of the patients had to stop anti-TNF therapy despite a number of other therapeutic manipulations. Similarly, in our study, switching from infliximab to adalimumab improved the skin lesions only in one patient, while in another patient the skin lesions did not improve after switching from infliximab to adalimumab and then to certolizumab. Discontinuing anti-TNF therapy as a major part of treatment of anti-TNF antibody-induced palmoplantar pustulosis has also been described in the Mayo study and other case reports. Overall, all currently approved anti-TNF inhibitors may cause psoriasiform skin lesions, suggesting that this is a class-related side effect. In our study, the majority of patients with skin lesions were treated with infliximab. However, this may reflect the earlier approval and longer use of infliximab, which is also shown by the fact that more patients without skin lesions were treated with infliximab than adalimumab.
To unravel genetic risk factors associated with anti-TNF-induced psoriasiform skin lesions, we performed a detailed genotyping analysis of IBD- and psoriasis-associated IL23R and IL12B gene variants. Although there were nominally no significant differences in the minor allele frequencies of these gene variants when anti-TNF-treated patients with IBD with and without skin lesions were compared, all patients with severe psoriasiform skin lesions and/or anti-TNF-induced alopecia requiring ustekinumab therapy were G/G wildtype carriers for the rare coding IL23R variant rs11209026 (p.Arg381Gln). In contrast to carriers of the rare minor A allele, this is associated with higher Th17 cytokine production, suggesting a role of Th17 cells in the pathogenesis of these skin lesions. A role for IL23R in the disease pathogenesis of psoriasiform skin lesions has also been suggested by a study of a smaller paediatric IBD cohort.
Currently, the pathogenesis of psoriasiform skin lesions caused by anti-TNF therapy is only poorly understood. Considering that TNF-α plays a key role in the pathogenesis of IBD and psoriasis, the occurrence under anti-TNF therapy seems to be paradoxical. According to one hypothesis, plasmacytoid dendritic cells (pDCs) may play a role in the formation of anti-TNF antibody induced psoriasiform lesions. pDCs have been described by us in psoriasis lesions for the first time and are known producers of IFN-α. TNF-α inhibits pDC maturation from haematopoietic progenitor cells and consequently inhibits IFN-α production. Therefore, anti-TNF treatment may result in unlimited IFN-α production by pDCs. In agreement with this hypothesis, we found IFN-α protein expression in all patients who underwent skin biopsy for sampling anti-TNF-induced psoriasiform skin lesions. Similarly, increased IFN-α expression has been found in the skin vasculature and in perivascular lymphocytic infiltrates of skin lesions in patients treated with anti-TNF antibodies. However, our immunohistochemical staining also demonstrates TNF-α expression in the majority of patients. This suggests that despite TNF-α inhibition being a trigger for psoriasiform skin lesions, TNF-α participates in the secondary inflammatory skin reaction which is similar to genuine psoriasis and consistent with our analysis of TNF-α expression in patients with genuine psoriasis (figure 12G). Other studies suggested that altered lymphocyte migration caused by anti-TNF treatment may also contribute to skin lesions through the expression of CXCR3 ligands. We recently demonstrated increased expression of CXCR3 ligands in active IBD, which may be an additional risk factor for developing these skin lesions.
In addition to these findings, our histological analysis revealed for the first time an increased number of IFN-γ-secreting Th1 and IL-17-/IL-22-secreting Th17 cells in anti-TNF-induced psoriasiform skin lesions. This is similar to the cytokine profile in genuine psoriasis, in which increased expression of the Th17 cytokines IL-17A and IL-22 has been demonstrated. Importantly, we found strong IL-17A expression significantly more often in very severe psoriasiform skin lesions requiring ustekinumab therapy than in less severe lesions responding to topical therapy. Two very recent studies demonstrated that antibody therapy directed against IL-17A or its receptor IL-17RA is effective in psoriasis. In addition to IL-17A, IL-22 plays a key role in the pathogenesis of psoriasis and increases the expression of proinflammatory genes in keratinocytes. A clinical trial evaluating fezakinumab (ILV-094), an antibody directed against IL-22, has been initiated in patients with psoriasis. Psoriasis is histologically characterised by hyperplasia of the epidermis (acanthosis), infiltration of leukocytes into the dermis and epidermis, and dilation and growth of blood vessels, all features found in many of our patients who underwent skin biopsy sampling. A recent study demonstrated that IL-22 mediates IL-23-induced acanthosis and dermal inflammation through the activation of STAT3 (signal transduction and activators of transcription 3) in vivo, providing a rationale for anti-IL-23 and anti-IL-22 therapy in psoriasis. Based on our detailed histopathological analysis, we hypothesise that Th1 and Th17 cells play a major role in the disease pathogenesis of anti-TNF-induced psoriasiform skin lesions. Additional studies are required to clarify the effects of type I interferons on Th17 cytokines in the disease pathogenesis of these lesions. For example, worsening of Th17 cell-mediated psoriasis has been reported in patients with psoriasis and hepatitis C treated with type I IFN, while IFN-β may inhibit Th17 cell differentiation in mice.
This study is the first detailed report on the successful use of the anti-IL-12/IL-23 antibody ustekinumab for anti-TNF-induced psoriasiform skin lesions. Ustekinumab has been approved for the treatment of plaque psoriasis in the USA and Europe. Pilot trials and a large study indicate some efficacy in CD. In all nine patients treated with ustekinumab, psoriasiform skin lesions improved dramatically after the first two injections. Moreover, in the majority of these patients, CD activity was controlled with ustekinumab. However, it is likely that CD requires a higher ustekinumab dose than psoriasis for maintenance of remission, which is currently being investigated in ongoing trials. Inhibition of IL-23 also limits IL-17A and IL-22 production and Th17 cytokine-induced skin and gut inflammation, while inhibition of IL-12 limits Th1-induced IFN-γ expression. Due to the limited number of patients with psoriasiform skin lesions and considering the severity of skin lesions and the complicated IBD in most patients, our study does not contain a comparison group in which anti-TNF therapy was stopped. However, the results of Rahier et al suggest that stopping anti-TNF therapy may be effective in many patients. Interestingly, in one of the nine ustekinumab-treated patients with psoriasiform skin lesions, there was a slight recurrence of these lesions at the end of the ustekinumab injection interval, which suggests that—at least in some patients—stopping anti-TNF therapy is not sufficient to completely heal these lesions. This could also be the case in patients who convert to 'true' (genuine) psoriasis, triggered by anti-TNF therapy.
In conclusion, new onset psoriasiform skin lesions develop in approximately 5% of anti-TNF-treated patients with CD. Active smoking or a history of being a smoker is the strongest predictive factor for developing psoriasiform skin lesions. These lesions are characterised by IFN-α expression and infiltrates of IL-17A/IL-22-secreting Th17 cells and IFN-γ-secreting Th1 cells. Anti-IL-12/IL-23 antibody therapy is highly effective in treating anti-TNF-induced psoriasis and psoriasiform alopecia. Given the previously shown efficacy of anti-IL-12/IL-23 antibody therapy in CD, ustekinumab may be a suitable alternative to anti-TNF therapy in patients with CD with anti-TNF-induced psoriasiform skin lesions.
Discussion
In this study, we demonstrate that anti-TNF antibodies, which are approved for the treatment of psoriasis, may paradoxically cause psoriasiform skin lesions in patients with IBD. This study contributes significantly to our understanding of these lesions and differs from previous retrospective case series for a number of reasons. In contrast to previous studies, the data were collected prospectively and all patients with skin lesions were seen by the same board-certified dermatologist. This allowed for the calculation of incidence rates of these lesions. We identified smoking as the major risk factor for these lesions. In addition, this study contains a detailed histopathological analysis and provides, for the first time, evidence that Th1 and Th17 cells play a key role in the pathogenesis of these lesions, suggesting similarities in the pathogenesis of anti-TNF-induced psoriasiform skin lesions and that of psoriasis. We also provide first proof of principle that anti-IL-12/anti-IL-23 antibody therapy, which is directed against Th1 and Th17 cells, is highly effective in patients with severe anti-TNF-induced psoriatic skin lesions. In addition, we performed a detailed genotype analysis of IBD- and psoriasis-associated IL23R, IL23, IL12B gene variants in patients with anti-TNF-induced skin lesions.
Psoriasiform and eczematiform skin lesions are the most frequently observed dermatological adverse events in patients treated with anti-TNF antibody. Several case series analysing severe skin lesions in patients with IBD caused by anti-TNF inhibitors have been published. Due to the retrospective nature of the majority of previous studies, the exact prevalence of psoriasiform skin lesions in patients receiving anti-TNF antibodies is largely unknown. In our prospective study, almost 5% of all anti-TNF-treated patients developed psoriasiform skin lesions, which is consistent with data derived from anti-TNF-treated patients with rheumatoid arthritis. Rahier et al extrapolated data from a French IBD centre and suggested that the risk of developing inflammatory skin lesions (psoriasiform or eczematiform) is around 5% in anti-TNF-treated patients with IBD and the definitive need to withdraw anti-TNF treatment due to uncontrolled skin lesions is around 1%. Similarly, in our study, in 7 of 434 anti-TNF-treated patients with IBD (1.6%) anti-TNF treatment had to be stopped due to severe skin lesions. In our study, most patients with psoriasiform lesions had palmoplantar psoriasis, which was also one of the most common skin manifestations in other studies.
Similar to our study, in which 90.5% of patients with anti-TNF-induced psoriasis had CD, the majority of patients in other studies were diagnosed with CD and not UC. This is in agreement with the clinical observation that there is a stronger overlap between psoriasis and CD compared with UC, which may be related to the stronger association of CD and psoriasis with IL23R and IL12B SNPs than observed in UC. However, considering the later approval for infliximab and adalimumab for the treatment of UC (compared with CD), this may partially reflect a prescription bias of anti-TNF inhibitors in patients with IBD.
Smokers seem to be especially prone to psoriasiform skin lesions. In our study, 76.2% of the patients with psoriasiform skin lesions were active smokers or ex-smokers. In multivariate analysis, being a smoker or having a history of smoking was the strongest predictive factor for developing psoriasiform skin lesions (p=0.007; OR 4.24, 95% CI 1.55 to 13.60). In addition, we identified an increased BMI as a risk factor for developing these lesions (p=0.029; OR 1.12, 95% CI 1.01 to 1.24). Interestingly, smoking and an increased BMI have also been shown to increase the risk for psoriasis, suggesting similarities in the disease pathogenesis of anti-TNF-induced psoriasiform skin lesions and psoriasis.
We had to stop anti-TNF therapy in 7 of 21 patients with skin lesions (33.3%) due to the severity of lesions and the lack of efficacy of topical therapy. In the study by Rahier et al, 40% of the patients had to stop anti-TNF therapy despite a number of other therapeutic manipulations. Similarly, in our study, switching from infliximab to adalimumab improved the skin lesions only in one patient, while in another patient the skin lesions did not improve after switching from infliximab to adalimumab and then to certolizumab. Discontinuing anti-TNF therapy as a major part of treatment of anti-TNF antibody-induced palmoplantar pustulosis has also been described in the Mayo study and other case reports. Overall, all currently approved anti-TNF inhibitors may cause psoriasiform skin lesions, suggesting that this is a class-related side effect. In our study, the majority of patients with skin lesions were treated with infliximab. However, this may reflect the earlier approval and longer use of infliximab, which is also shown by the fact that more patients without skin lesions were treated with infliximab than adalimumab.
To unravel genetic risk factors associated with anti-TNF-induced psoriasiform skin lesions, we performed a detailed genotyping analysis of IBD- and psoriasis-associated IL23R and IL12B gene variants. Although there were nominally no significant differences in the minor allele frequencies of these gene variants when anti-TNF-treated patients with IBD with and without skin lesions were compared, all patients with severe psoriasiform skin lesions and/or anti-TNF-induced alopecia requiring ustekinumab therapy were G/G wildtype carriers for the rare coding IL23R variant rs11209026 (p.Arg381Gln). In contrast to carriers of the rare minor A allele, this is associated with higher Th17 cytokine production, suggesting a role of Th17 cells in the pathogenesis of these skin lesions. A role for IL23R in the disease pathogenesis of psoriasiform skin lesions has also been suggested by a study of a smaller paediatric IBD cohort.
Currently, the pathogenesis of psoriasiform skin lesions caused by anti-TNF therapy is only poorly understood. Considering that TNF-α plays a key role in the pathogenesis of IBD and psoriasis, the occurrence under anti-TNF therapy seems to be paradoxical. According to one hypothesis, plasmacytoid dendritic cells (pDCs) may play a role in the formation of anti-TNF antibody induced psoriasiform lesions. pDCs have been described by us in psoriasis lesions for the first time and are known producers of IFN-α. TNF-α inhibits pDC maturation from haematopoietic progenitor cells and consequently inhibits IFN-α production. Therefore, anti-TNF treatment may result in unlimited IFN-α production by pDCs. In agreement with this hypothesis, we found IFN-α protein expression in all patients who underwent skin biopsy for sampling anti-TNF-induced psoriasiform skin lesions. Similarly, increased IFN-α expression has been found in the skin vasculature and in perivascular lymphocytic infiltrates of skin lesions in patients treated with anti-TNF antibodies. However, our immunohistochemical staining also demonstrates TNF-α expression in the majority of patients. This suggests that despite TNF-α inhibition being a trigger for psoriasiform skin lesions, TNF-α participates in the secondary inflammatory skin reaction which is similar to genuine psoriasis and consistent with our analysis of TNF-α expression in patients with genuine psoriasis (figure 12G). Other studies suggested that altered lymphocyte migration caused by anti-TNF treatment may also contribute to skin lesions through the expression of CXCR3 ligands. We recently demonstrated increased expression of CXCR3 ligands in active IBD, which may be an additional risk factor for developing these skin lesions.
In addition to these findings, our histological analysis revealed for the first time an increased number of IFN-γ-secreting Th1 and IL-17-/IL-22-secreting Th17 cells in anti-TNF-induced psoriasiform skin lesions. This is similar to the cytokine profile in genuine psoriasis, in which increased expression of the Th17 cytokines IL-17A and IL-22 has been demonstrated. Importantly, we found strong IL-17A expression significantly more often in very severe psoriasiform skin lesions requiring ustekinumab therapy than in less severe lesions responding to topical therapy. Two very recent studies demonstrated that antibody therapy directed against IL-17A or its receptor IL-17RA is effective in psoriasis. In addition to IL-17A, IL-22 plays a key role in the pathogenesis of psoriasis and increases the expression of proinflammatory genes in keratinocytes. A clinical trial evaluating fezakinumab (ILV-094), an antibody directed against IL-22, has been initiated in patients with psoriasis. Psoriasis is histologically characterised by hyperplasia of the epidermis (acanthosis), infiltration of leukocytes into the dermis and epidermis, and dilation and growth of blood vessels, all features found in many of our patients who underwent skin biopsy sampling. A recent study demonstrated that IL-22 mediates IL-23-induced acanthosis and dermal inflammation through the activation of STAT3 (signal transduction and activators of transcription 3) in vivo, providing a rationale for anti-IL-23 and anti-IL-22 therapy in psoriasis. Based on our detailed histopathological analysis, we hypothesise that Th1 and Th17 cells play a major role in the disease pathogenesis of anti-TNF-induced psoriasiform skin lesions. Additional studies are required to clarify the effects of type I interferons on Th17 cytokines in the disease pathogenesis of these lesions. For example, worsening of Th17 cell-mediated psoriasis has been reported in patients with psoriasis and hepatitis C treated with type I IFN, while IFN-β may inhibit Th17 cell differentiation in mice.
This study is the first detailed report on the successful use of the anti-IL-12/IL-23 antibody ustekinumab for anti-TNF-induced psoriasiform skin lesions. Ustekinumab has been approved for the treatment of plaque psoriasis in the USA and Europe. Pilot trials and a large study indicate some efficacy in CD. In all nine patients treated with ustekinumab, psoriasiform skin lesions improved dramatically after the first two injections. Moreover, in the majority of these patients, CD activity was controlled with ustekinumab. However, it is likely that CD requires a higher ustekinumab dose than psoriasis for maintenance of remission, which is currently being investigated in ongoing trials. Inhibition of IL-23 also limits IL-17A and IL-22 production and Th17 cytokine-induced skin and gut inflammation, while inhibition of IL-12 limits Th1-induced IFN-γ expression. Due to the limited number of patients with psoriasiform skin lesions and considering the severity of skin lesions and the complicated IBD in most patients, our study does not contain a comparison group in which anti-TNF therapy was stopped. However, the results of Rahier et al suggest that stopping anti-TNF therapy may be effective in many patients. Interestingly, in one of the nine ustekinumab-treated patients with psoriasiform skin lesions, there was a slight recurrence of these lesions at the end of the ustekinumab injection interval, which suggests that—at least in some patients—stopping anti-TNF therapy is not sufficient to completely heal these lesions. This could also be the case in patients who convert to 'true' (genuine) psoriasis, triggered by anti-TNF therapy.
In conclusion, new onset psoriasiform skin lesions develop in approximately 5% of anti-TNF-treated patients with CD. Active smoking or a history of being a smoker is the strongest predictive factor for developing psoriasiform skin lesions. These lesions are characterised by IFN-α expression and infiltrates of IL-17A/IL-22-secreting Th17 cells and IFN-γ-secreting Th1 cells. Anti-IL-12/IL-23 antibody therapy is highly effective in treating anti-TNF-induced psoriasis and psoriasiform alopecia. Given the previously shown efficacy of anti-IL-12/IL-23 antibody therapy in CD, ustekinumab may be a suitable alternative to anti-TNF therapy in patients with CD with anti-TNF-induced psoriasiform skin lesions.
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