Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract that affect approximately 10 million patients worldwide (1, 2). The introduction of biologics has dramatically transformed the therapeutic landscape of IBD. Among these, anti-tumor necrosis factor (anti-TNF), such as infliximab and adalimumab, are most extensively used in daily practice for a couple of decades (3). Accumulative evidence has demonstrated that anti-TNF can control the disease activity rapidly, exert a steroid-sparing effect, promote mucosal healing, improve the quality of life, and reduce the risk of surgery as well (3, 4).

With increasing use of these agents, however, some paradoxical inflammations, involving the skin, joints and lungs, have been described and received increasing attention in recent years (5). Of these, paradoxical psoriasis or psoriasiform lesion induced by anti-TNF therapies is one of the most extended concerned topics worldwide. Generally, anti-TNF treatments are commonly used for psoriasis therapy, but psoriasis and psoriasiform skin lesions are sometimes observed in IBD patients receiving anti-TNF therapies. Overall, IBD patients treated with anti-TNF therapy have a 2.4-fold increased risk of paradoxical psoriasis compared with nonusers of anti-TNF (6). Meanwhile, there is high inconsistency in the results of previous studies on the incidence of psoriasis or psoriasiform lesions in IBD patients with exposure to anti-TNF, varying from 1% (6) to more than 30% (7). The relatively small sample sizes and limited number of events lead to significant variation and imprecise incidence estimates and further preclude robust conclusions to be drawn from any of the individual studies. On the other hand, currently, the knowledge about the risk factor for psoriasis or psoriasiform lesions secondary to anti-TNF therapy in IBD patients is limited and contradictory—for example, some studies have shown gender, smoking, and concomitant immunosuppressive agents to be associated with an increased risk of developing anti-TNF-induced psoriasis, while others have not (8–16).

To date, no comprehensive meta-analysis investigating the incidence estimates and risk factors for anti-TNF-induced psoriasis is currently available. To fill the gap, the present study is intended to precisely quantify the incidence of and risk factors for developing anti-TNF-induced psoriasis or psoriasiform lesions in IBD patients.

This article was carried out and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (17). The methods were stipulated in a protocol that was registered with PROSPERO (CRD42021233695).

To our knowledge, this is the first systematic review and meta-analysis to comprehensively investigate the incidence of and risk factors for psoriasis or psoriasiform lesions secondary to anti-TNF therapy in IBD patients. The overall estimated pooled incidence was 6.0% psoriasis and/or psoriasiform lesions in IBD patients following anti-TNF therapy. Regarding risk factors, female, younger age at anti-TNF therapy initiation, smoking, and adalimumab or certolizumab usage were significantly associated with an increased risk of developing psoriasis or psoriasiform lesions during anti-TNF therapy in IBD patients. These findings have the potential to inform clinical practice for more individualized decisions or precautions and may help us to understand the mechanism of this paradoxical phenomenon.

Anti-TNF agents have assumed the dominant position in the treatment of IBD over the past couple of decades. A large body of evidence confirms the overall good safety profile of the anti-TNF agents. However, with the increased use of these agents, paradoxical inflammation or autoimmune diseases induced by anti-TNF agents have been continuously reported, including cutaneous, articular, ocular, and neurological involvements (41, 42). Of these, paradoxical psoriasis or psoriasiform lesions, being the most prevalent and well-known paradoxical adverse events associated with anti-TNF agents, have been under intense investigation in recent years. At present, paradoxical psoriasis or psoriasiform lesions can no longer be considered rare in clinical routine, with incidence estimates of greater than 20% with the use of anti-TNF agents in some research. For the incidence of psoriasis/psoriasiform rash, our results, overall, were comparable to the results from the 2021 meta-analysis (43). The primary outcome of dermatological reactions in IBD patients receiving anti-TNF therapy from 26 studies was 19.4% (95% CI: 15.2–24.4%, I ² = 95%) in this meta-analysis. In the secondary outcome of psoriasis/psoriasiform rash, there was a pooled incidence of 5.6% (95% CI: 4.2–7.4%, I ² = 95%), with 6.1% (95% CI: 3.4–10.6%, I ² = 96%) for infliximab therapy and 5.9% (95% CI: 2.5–13.5, I ² = 93%) for adalimumab therapy. In addition to this, our work has reported more detailed and more specific information on anti-TNF associated psoriasis/psoriasiform rash. In the meta-regression and subgroup analyses, we also noticed that the regions and population contributed to the heterogeneity. Taken together, gastroenterologists should be aware of the paradoxical phenomenon, and the current findings could be instrumental in guiding therapeutic decision in clinical routine.

Currently, the molecular mechanisms and pathogenesis of paradoxical psoriasis/psoriasiform rash associated with anti-TNF agents are poorly understood, and multiple factors might be involved, including the genetic predisposition, preexisting autoimmune condition, and increased secretion and imbalance of cytokines and cells (interferon−α, Th1, Th2, Th17 cytokines, etc.). Clinically, the risk factors for developing psoriasis/psoriasiform rash after anti-TNF therapy are under exploration but are inconclusive. The present study, for the first time, has systematically reviewed the literature surrounding the risk factors. The meta-analyses revealed a statistically increased risk of developing psoriasis or psoriasiform lesions during anti-TNF therapy in IBD patients who are female, of a young age at anti-TNF therapy initiation, smoking, and using adalimumab or certolizumab. In the general population, psoriasis can manifest at any age, but with the highest peak between the ages of 20 and 40 years (44). The function of the immune system, and so does autoimmunity, is affected by various factors, including age (45). Overall, age is closely related to the strength of the immune system response, which is expected to decline in senescence (46, 47). From this aspect, the association between advanced age and low risk of psoriasis or psoriasiform lesions secondary to anti-TNF therapy can also be, in part, instinctively understood. In this study, we found that smoking, past and present, is the major risk factor for developing psoriasis during anti-TNF treatment in IBD patients. In fact, the adverse effects of smoking on psoriasis onset have been documented in the general population. The possible pathophysiological mechanisms of the associations included oxidative stress and free radical damage induced by smoking, which could trigger a cascade of systemic inflammation and the subsequent development of psoriasis (48, 49). However, it is still challenging to understand whether or how smoking work together with TNF blockade to orchestrate the psoriasis occurrence. In vitro, cigarette smoke chemical components could activate nuclear factor kappa-B activation and proinflammatory cytokine production, including IL-1β and IL-6 (50). The full blockade of TNF-α may impair the homeostasis of normal skin and cause an imbalance in cytokines and cells, which may be further exacerbated by the presence of smoking, and finally paradoxical adverse events occur (50). For paradoxical skin inflammation, the IFN-α pathway was considered to play a key role. However, cigarette smoking was found to decrease the production of IFN-α and increase the production of IFN-β in vitro (51). Unraveling the synergistic effect between smoking and TNF blockade on the incidence of paradoxical psoriasis can be extremely complex in people with IBD, yet smoking cessation before starting anti-TNF therapy merits consideration in IBD patients from the perspective of decreasing the risk of paradoxical adverse events. In addition, current evidence suggests that paradoxical inflammation during treatment with anti-TNF agents seems to be a drug class effect. In the present study, the significantly higher risk of adalimumab or certolizumab therapy than infliximab therapy was identified, although both of them were associated with an increased risk of paradoxical psoriasis or psoriasiform skin lesions. In fact, potential differences between adalimumab and infliximab in IBD have been reported. In a nationwide cohort study of biologic-naive adults with UC, the adalimumab-treated patients showed a substantially higher rate of all-cause hospitalization and serious infection requiring hospitalization and a trend toward a higher rate of UC-related hospitalization (52). Besides these, infliximab drug levels were found to be associated with the depth of remission in patients with CD, but no such relationship was detected for adalimumab (53). However, there is no plausible mechanism evidence to explicitly explain the difference among different types of anti-TNF-associated psoriasis or psoriasiform rash. Future clinical and basic science studies are needed to experimentally validate the presented findings.

However, there were several limitations to our study. First, due to the nature of observational design in the original studies, the present study is vulnerable to potential biases (information or selection bias), which cannot allow us to conclude definite causal relationships. Second, the heterogeneity for the pooled incidence among the studies was very high. For this, we performed a series of subgroup analyses, meta-regression, and risk factor exploration. To a large extent, they could explain the source of heterogeneity. Third, various diagnosis criteria of psoriasis or psoriasiform skin lesions were applied in the included studies, mostly by interview or read codes rather than by dermatologists. Establishing a close collaboration between gastroenterologists and dermatologists is necessary to overcome this limitation in the future. Fourth, not all studies made enough adjustment for potential confounders, and we cannot fully unify the confounders, which can potentially lead to either an overestimation or an underestimation of the associations. Lastly, despite all the potential risk factors evaluated, for some of them, especially for disease activity, cumulative anti-TNF dosages were only included into the systematical review, and further investigations are required to explore their association.

In summary, the overall estimated pooled incidence of psoriasis/psoriasiform lesions secondary to anti-TNF therapy was 6% in IBD patients. Female, young age at anti-TNF therapy initiation, smoking, ileocolonic CD, and adalimumab or certolizumab use were associated with a substantially increased risk of developing psoriasis or psoriasiform lesions during anti-TNF therapy. These findings have the potential to inform clinical practice for more individualized decisions or precautions and may help us to understand the mechanism of this paradoxical phenomenon.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

ZZ conceptualized the study, participated in its design and coordination, and critically revised the manuscript. WX and SX contributed to data collection, analysis, and interpretation and drafted the manuscript. HH contributed to the process of data collection as a study investigator. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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