What Is Known
- The prevalence of paradoxical psoriasis has been estimated between 1.6% and 22% in adults with inflammatory bowel disease treated with infliximab, and 8% in children.
What Is New
- In this retrospective study, among 147 children treated with infliximab for inflammatory bowel disease with a median follow-up of 2 years, 20 patients (13,6%) developed a paradoxical psoriasis.
- All children in the psoriasis group were followed for Crohn disease (P = 0.05) and perianal location was more frequent (P = 0.03).
- At time of skin lesions occurrence, the intestinal inflammation is low and Crohn disease is usually well-controlled.
Infliximab (IFX), a chimeric monoclonal immunoglobulin G1 (IgG1) antibody against tumor necrosis factor α (TNFα), is effective for induction and maintenance of remission in adults (1,2) and children (3) with inflammatory bowel disease (IBD). Moreover, efficacy and safety profiles of IFX have been established for moderate-to-severe psoriasis (4). Nevertheless, IFX whenever used in IBD patients has been associated with psoriasis-like lesions called paradoxical psoriasis that occur during the maintenance phase of treatment (5–25). The pathophysiology of this paradoxical immune-mediated inflammatory disease is not well understood: decreased TNF seems to induce the activation of autoreactive T cells and an increased interferon-α activity, as well as increased levels of other pro-inflammatory cytokines like interleukin-12, -17, and -23 (6–11). One issue of those skin lesions is that they may lead to impaired quality of life, poor self-image, and breach of trust in treatment.
In adults with IBD, the prevalence of paradoxical psoriasis has been estimated between 1.6% and 22% (12–18). In almost half of these patients, the switch for another anti-TNFα therapy was followed by a recurrence of skin lesions (13). Only few pediatric studies have been published in the last years (23–25). Infliximab-induced psoriasis has been described in 8% of children with IBD, after a median of 13 infusions (23). That pediatric infliximab-induced psoriasis seem to occur in a particular genetic background: polymorphisms in the IL-23R gene could have a role in the pathogenesis of this paradoxical process, which presently remains unexplained (25).
Little is known about the clinical and/or biological factors associated with paradoxical psoriasis in PIBD. The aims of this study were to report the prevalence and risk factors of infliximab-induced psoriasis in a pediatric population with IBD.
PATIENTS AND METHODS
All patients ages from 2 to 18 years with Crohn disease (CD) or ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014 were considered for inclusion in this retrospective study. For all children, the treatment was initiated and followed at the pediatric gastroenterology department at Robert Debré Teaching Hospital, Paris, France. Children who received IFX less than 45 days or who were treated on-demand; patients whose treatment had been initiated in another centre and patients whose medical record was incomplete were excluded.
During the study period, all patients received IFX according to the same protocol: an induction therapy with IFX (4 h infusion at a dose of 5 mg/kg at weeks 0, 2 and 6), followed by maintenance therapy (2 h infusion of 5 mg/kg every 8 weeks). Dosing could be adapted according to clinical condition of the child, with a maximum dose of 10 mg/kg, as was the range between 2 infusions, which could vary from 4 to 8 weeks. Each IFX infusion was preceded by a premedication with intravenous hydrocortisone (200 mg) and intravenous dexchlorphéniramine (5 mg) to minimize the risk of acute infusion reaction (26).
The study was approved by the Institutional Review Boards (IRB 2014/123) for the ethical approval and the French national data protection agency (Commission nationale de l’informatique et des libertés n°1758964v0).
Data were anonymously collected from medical files. The baseline characteristics recorded for each patient included: sex, age at IBD onset, age at inclusion, duration of disease, type of IBD, IBD classification according to Paris classification (27), previous treatments (drugs and/or surgery), extraintestinal manifestations, and reasons for anti-TNFα initiation. At baseline and at each infusion visit, disease activity was monitored using the Pediatric Crohn disease Activity Index (PCDAI) (28) for CD and the Pediatric Ulcerative Colitis Activity Index (PUCAI) (29) for UC.
Cases of paradoxical psoriasis, diagnosed by a dermatologist in all cases and defined by new-onset inflammatory skin lesions, which resemble psoriasis, were collected in patient's record. It was considered to be IFX-induced if the patient was free of any skin lesions before the IFX initiation.
Blood samples were obtained for each patient at each visit and trough levels to IFX (IFX-TL) and antibodies to IFX (ATI) were recorded. IFX-TL and ATI were measured blindly to clinical data, as previously described (30). IFX concentrations in the serum were measured using a solid phase ELISA method: IFX was captured with plate-bound recombinant TNF-α and detected with a horseradish peroxidise-conjugated anti-human IgG1 (Caltag Laboratories, CA).
Children were classified in 2 groups according to the presence of remission or not at week 6. Remission was defined by a PCDAI or a PUCAI under or equal to 10.
Categorical variables were described as frequencies and percentages. Continuous variables were described as the median and interquartile range (IQR), or mean and standard deviation, according to the normality. Children with IFX-induced psoriasis were compared with children without using chi-square test or Fisher exact test for categorical variables and nonparametric test for continuous variables (Mann-Whitney-Wilcoxon). A P-value of <0.05 was considered as significant (2-sided). The time between IFX initiation and psoriasis occurrence was estimated using the Kaplan-Meier method. Statistical analyses were performed using SAS analysis statistical software (version 9.4; SAS institute, Cary, NC).
Among the 147 patients included (123 CD and 24 UC, Fig. 1), 138 (115 CD and 23 UC) followed a maintenance phase after week 14. Patients’ characteristics are summarized in Table 1. The median age at IFX initiation was 14 years, in average 2 years after diagnosis. The median follow-up after inclusion was 23.9 months (IQR: 11.6; 36.5).
During follow-up, 20 patients (13.6%) experienced an IFX-induced psoriasis (Fig. 1). Among them, 14 (70%) were in remission when psoriasis occurred. The median time of psoriasis diagnosis was at the eighth injection (IQR: 6; 15), corresponding to 355 days (IQR: 239; 532) after IFX initiation. Kaplan-Meier estimates of the probability of psoriasis were 15% (95% confidence interval [95% CI]: 9%–23%), at 2 years and 23% (95% CI: 14%–36%) at 4 years and 6 years. The scalp was the most common area of involvement. Other involved areas included the face, postauricular areas, and more rarely axillar, chest, abdominal areas, or genitals.
Among the patients with psoriasis, 4 (20%) received a combo-therapy with 6-mercaptopurine (n = 2), azathioprine (n = 1), or methotrexate (n = 1). The median IFX-TL was 4.7 μg/mL (IQR: 1.8; 9.6) when psoriasis occurred, and 4.1 μg/mL (IQR: 2.1; 8.8) at the previous visit, a value not significantly different from the nonpsoriasis group. Median ATI rate was 0% (IQR: 0; 18.5).
All psoriasis patients were supported by local treatments. No patients discontinued biotherapy because of their skin lesions.
Comparison Between Patients With and Without Psoriasis
Comparisons between patients with (n = 20) and without (n = 127) psoriasis are reported in Table 2. All children in the psoriasis group were followed for CD (P = 0.05). Among CD patients, perianal lesions were more frequent in the psoriasis group (P = 0.03). Patients diagnosed with psoriasis had a longer follow-up (30.4 months [IQR: 15.9; 45.1]) than those without (19.2 months [IQR: 7.5; 32.4]; P = 0.02), and therefore, a greater number of injections (20 [IQR: 12; 30] vs 14 [IQR: 7; 20]; P < 0.01). The association between psoriasis and the early age at diagnosis (less than 10 years) but not the age at induction was borderline significant (P = 0.06). At the end of induction (week 6), there was significantly less children under combotherapy in the psoriasis group (n = 7, 35%) than in the control group (n = 78, 62%, P = 0.02).
Comparison of Probability of Psoriasis in Responders and Nonresponders
At week 6, 2 populations were identified: 67 full responders defined by a clinical remission and 71 nonresponders or partial responders who maintained an activity score above 10. An univariate Kaplan-Meier analysis found a probability of psoriasis at 2 years not significantly different between the remission group (21%; 95% CI 12–37) and the nonresponse or partial response group (10%; 95% CI 4–20). At 4 and 6 years, the frequency of psoriasis was higher in the first group (36%; 95% CI 21–56) than in the second one (10%; 95% CI 4–20).
In this retrospective study, 147 children with IBD were treated with IFX with a median follow-up of 2 years. Among them, 20 patients (13.6%) developed a paradoxical psoriasis. Psoriasis induced by IFX was the most common adverse event (data not shown). A young age at diagnosis was borderline significant in our study. The young age at anti TNF-α initiation was a risk factor for paradoxical psoriasis in other reports (20,31). As a consequence, the observed percentage of psoriatic patients in our study is among the highest values previously reported (7–11,23).
Pediatric paradoxical psoriasis occurred only in CD patients. Other studies provided similar findings: patients suffering from CD were more likely to have skin lesions (19) than UC (20). Furthermore, our data suggests that perianal lesions are a risk factor of psoriasis in CD patients. In a previous work, perianal disease was associated with a 3.5 times higher risk for developing TNF-antagonist-related psoriasis (32). An association with perianal disease was also reported by Barthel et al (33). No clear explanation is available to explain this association. An inflammation of the skin appears to be a common finding for perianal CD and psoriasis. This may suggest a shared cutaneous immune response in both conditions. A genetic polymorphism of the interleukin 23 receptor genotype has been associated with psoriasis lesions in IBD patients (25). Finally, a good control by ustekinumab (an anti-IL12/IL23 antibody) of psoriasis lesions induced by anti-TNF-a therapy has been reported (11).
Paradoxical psoriasis most often occurred within the first 2 years of biotherapy: the timing of psoriasis occurrence was in median at 1 year after the initiation of the therapy, which corresponds to the eighth injection (IQR: 6; 15). After the fourth year, we did not observe any new incident case but our series is limited and the CI of the observed values is thus large. The median latency period between the administration of IFX and the development of psoriasis is comparable in other studies with a median time of 12 months (34) and 8 to 13 IFX infusions (23,32).
At time of skin lesion occurrence, the intestinal inflammation is low and CD usually well-controlled (35). We confirm here that psoriatic patients are under prolonged remission when psoriasis occurs and thereafter. As a consequence, psoriasis patients were treated during a longer period than the rest of the cohort with (30.4 [IQR: 15.9; 45.1] against 19.2 [IQR: 7.5; 32.9] months, P < 0.015).
As previously reported, IFX-TL does not seem to play a role in the pathogenesis of psoriasis (32). The role of concommitant immunosuppressants is not as clear as in other studies. In our study, patients under combo therapy at W6 are more frequent in the group with psoriasis compared with the group control (P = 0.02). However, this trend is not found at other study times like W0, W2, or W14 suggesting that no clear conclusion must be drawn. In the same line, a reduced risk of paradoxical psoriasis was reported in patients under combo-therapy (21).
In this cohort, all psoriasis cases were successfully treated with topical steroids alone or in combination with vitamin D analogs. Consistently, only few cases necessitated IFX discontinuation in the literature (24).
In conclusion, paradoxical psoriasis appears as the most frequent side effect in pediatric CD treated with IFX. Perianal lesions are a risk factor of this drug side effect. Although no clear explanation is provided, it is worth further research to clarify the mechanism for this association. It rarely leads to discontinuation of IFX, which remains most often efficient to sustainably control the intestinal inflammation.
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