Psoriasis, a common chronic skin disease affecting approximately 2% of the global population, is characterized by elevated levels of pro-inflammatory cytokines (1–3). In addition to skin lesions, 30% of psoriasis patients have joint lesions and will progress to psoriatic arthritis (PsA) (4, 5). PsA is an inflammatory joint disease associated with psoriasis, which can cause symptoms such as joint pain, swelling, stiffness, and limited mobility (6, 7).Current management of psoriasis encompasses topical agents, biologic therapies, and phototherapy. Targeted therapies have gained widespread adoption due to their high selectivity, rapid onset, and favorable safety profiles (8). The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway is an important signaling pathway involved in the pathogenesis of psoriasis and PsA. This pathway transmits extracellular signals to the cell nucleus through transmembrane receptors and mediates a series of physiological and pathological processes (9, 10).

The JAK family consists of four members including JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). By inhibiting the cytokine pathway, JAK inhibitors can effectively reduce the expression of key cytokines involved in the development of psoriasis and PsA (11–13). Currently, several JAK inhibitors have been approved for the treatment of psoriasis and PsA (14).Tofacitinib (approved by the FDA for PsA in 2017, a JAK1/JAK3 inhibitor) (15) and upadacitinib (approved by the FDA for PsA in 2021, a selective JAK1 inhibitor) can regulate the immune signaling pathway, and they would not cause renal and hepatic toxicity like cyclosporine A and methotrexate (16). Deucravacitinib, a TYK2 inhibitor, was approved by the FDA for moderate-to-severe plaque psoriasis in 2022 (17), which significantly improves skin clearance and disease severity (18).

JAK inhibitors used for psoriasis and PsA are associated with characteristic adverse events (AEs), including headache, diarrhea, upper respiratory infections, myelosuppression, and rash (16). With the continuous promotion and application of these drugs, some AEs may remain newly identified or underreported. Currently, there is no systematic report on safety signals of JAK inhibitors used in psoriasis and PsA. Due to the differences in the inhibitory targets and molecular activities of different JAK inhibitors, it is necessary to comprehensively investigate the safety profiles of individual drugs and conduct comparisons among patients with psoriasis and PsA.

Disproportionality analysis is a widely used method for establishing hypotheses about correlations between specified drugs and AEs, which involves signal detection through the review of individual case safety reports (ICSRs) and statistical analysis. The Food and Drug Administration Adverse Event Reporting System (FAERS) is the largest post-market surveillance program, which facilitates the early detection of AEs and the monitoring of newly launched drugs. It has been widely used to identify risk signals of AEs.

Achieving comprehensive disease control for psoriasis often requires therapies that can effectively manage both skin and joint symptoms simultaneously (16). Psoriasis and PsA share a common T-cell-mediated immunopathogenic mechanism (19), and a substantial proportion of patients with psoriasis eventually develop PsA (20), resulting in an overlap of these two conditions in clinical practice. Although the FDA has only approved the application of three JAK inhibitors for either psoriasis or PsA as one of their indications, off-label use targeting the other indication (psoriasis or PsA) has been observed in both clinical trials and clinical practice. Currently, existing clinical trials have confirmed the efficacy and safety of deucravacitinib in PsA, suggesting that it may become the first orally administered TYK2 inhibitor approved for PsA (21). Studies have found that tofacitinib has demonstrated positive effects on the treatment of chronic plaque psoriasis (22, 23), and it can serve as a therapeutic option for patients with psoriasis, with generally good tolerability (24). Furthermore, tofacitinib has been approved for the treatment of moderate to severe plaque psoriasis in Russia (25). Moreover, there have been reports of upadacitinib being used for the treatment of psoriasis (26–29). Importantly, JAK inhibitors have shown efficacy in clinical trials for both psoriasis and PsA (24, 30). In addition, several FAERS-based pharmacovigilance studies have analyzed psoriasis and PsA as a combined cohort when evaluating safety outcomes (31–33).

Based on these considerations, this study aimed to systematically analyze AEs associated with JAK inhibitors (deucravacitinib, upadacitinib, and tofacitinib) in patients with psoriasis and PsA as an integrated cohort using FAERS post-marketing surveillance data, while also conducting indication-stratified analyses to clarify potential differences between the two diseases.

The development of targeted therapies for psoriasis and PsA has significantly expanded treatment options, yet accompanying safety concerns require rigorous evaluation. This study systematically assesses the AE profiles of JAK inhibitors using FAERS data, providing critical post-marketing safety evidence to optimize risk-benefit decisions in clinical practice.

There have been some analyses of AEs regarding JAK inhibitors in previous studies (40, 41). However, limiting the indications is a commonly used method in pharmacovigilance analysis. Currently, no comprehensive safety assessment has been conducted on JAK inhibitors in psoriasis and PsA, and no direct comparative analysis between the two indications has been performed. To our knowledge, this is the most extensive and comprehensive pharmacovigilance study of JAK inhibitors used for psoriasis and PsA, providing certain references in clinical practice.

As a first-generation JAK inhibitor, tofacitinib exhibits broad activity across multiple JAK isoforms. Our analysis revealed a higher positive frequency of safety signals with tofacitinib compared to upadacitinib and deucravacitinib, consistent with its lower selectivity and longer post-marketing surveillance period. In contrast, upadacitinib (JAK1-selective) and deucravacitinib (TYK2-specific) demonstrated targeted kinase inhibition profiles that correlated with improved safety outcomes (42). And deucravacitinib exhibited fewer significant AE signals compared with upadacitinib and tofacitinib in this study. These distinct pharmacological properties may explain their differential AE profiles. Notably, deucravacitinib represents the first oral TYK2 inhibitor approved for psoriasis treatment, marking a significant advancement in immunomodulatory therapy. Its unique allosteric inhibition mechanism not only enhances treatment specificity but also shows promising translational potential for other immune-mediated diseases including PsA and systemic lupus erythematosus (21, 43).

Our analysis identified infections and infestations as class-wide AEs across all three JAK inhibitors. While these drugs effectively mitigate inflammation through pathway inhibition, their immunosuppressive properties may concurrently impair host defense mechanisms, potentially triggering paradoxical inflammatory reactions (44). Patients should be guided to seek medical help when encountering severe infections, and the discontinuation of JAK inhibitors should be considered. Due to its highly selective mechanism of action, deucravacitinib was associated with fewer reporting signals for infections and infestations compared to other JAK inhibitors. Furthermore, the positive signals for immune system disorders, hepatobiliary disorders, and musculoskeletal and connective tissue disorders were significantly lower with deucravacitinib than with tofacitinib and upadacitinib. However, patients treated with deucravacitinib exhibited a notably higher signal of skin and subcutaneous tissue disorders (e.g., acne, skin burning sensation, erythema, pruritus). The underlying mechanism remains unclear but may be related to immune-mediated alterations in the skin microbiome induced by deucravacitinib therapy (45). Since JAK inhibitors are administered orally, gastrointestinal-related AEs will accompany their use. Sensitivity analysis revealed that tofacitinib had higher gastrointestinal disorders signals than the other two drugs. In clinical practice, gastrointestinal disorder is the most common non-serious AE leading to tofacitinib discontinuation (46, 47).

SOC level analysis revealed pharmacovigilance signals for musculoskeletal and connective tissue disorders with upadacitinib and tofacitinib which were similar to the findings of other studies (48). The underlying mechanism may be related to the inhibition of JAK signaling pathways by these drugs. When JAK inhibitors interfere with these pathways, they can disrupt the normal balance of cytokines, potentially leading to abnormal tissue remodeling and inflammation in the musculoskeletal and connective tissue. Deucravacitinib showed no significant signal at this SOC level, but PT level analysis detected potential musculoskeletal AEs, including myalgia and blood creatine phosphokinase increased which were not previously documented in the prescribing information. This discrepancy is likely due to the relatively small number of musculoskeletal-related reports and the heterogeneity of PTs within this SOC, which diluted the disproportionate reporting when aggregated. Notably, this observation is also consistent with the unique pharmacological profile of deucravacitinib as a highly selective, allosteric TYK2 inhibitor (21, 43). Long-term clinical trial data for deucravacitinib have not revealed emergent and clustered musculoskeletal safety signals (45).Psoriasis and PsA patients frequently experience mood disorders such as anxiety and depression, often accompanied by pain, pruritus, and sleep disturbances (49). Moreover, some studies have found that oral anti-psoriasis drugs are significantly associated with a higher ROR of depression (50). Our study also identified new PT signals for nervous system disorders and psychiatric disorders associated with upadacitinib. These previously unreported AEs in the prescribing information warrant heightened clinical vigilance during subsequent therapeutic applications. Additionally, further research should be conducted to quantify and identify these unexpected risk factors. Notably, some AEs may not be directly attributable to the pharmacological intervention itself, but rather to the underlying disease or its complications (51). Nevertheless, these findings remain clinically noteworthy and warrant appropriate monitoring.

In the subgroup signal analysis comparing psoriasis and PsA, the overall patterns of safety signals appeared broadly similar across the two indications. However, metabolism and nutrition disorder reporting rates associated with upadacitinib were higher in psoriasis patients. Previous studies by Bostoen et al. (52) have similarly reported a higher prevalence of metabolic syndrome in psoriasis compared with PsA, a difference largely attributed to the significantly higher rates of abdominal obesity observed in psoriasis (52). Metabolic syndrome is recognized as one of the most common and clinically relevant comorbidities in psoriasis (53), and its development has been linked to several potential mechanisms, including endoplasmic reticulum stress, excessive release of proinflammatory cytokines, overproduction of reactive oxygen species, etc. (54).

Common AEs associated with JAK inhibitors include infections, neoplasms, musculoskeletal and connective tissue disorders, cardiovascular events, etc. (14, 55, 56) Zhao et al. (40) reported that the predominant AEs were related to skin and subcutaneous tissue disorders as well as infections and infestations in a study on the real-world safety of deucravacitinib. Upadacitinib was found to be associated with increased risks of respiratory events, cancer, musculoskeletal disorders, and infections (48). Tofacitinib has been linked to a higher risk of musculoskeletal disorders (48), systemic infections, tumor progression, and thromboembolic events (57). Consistent with these previous findings, our analysis revealed positive signals for musculoskeletal and connective tissue disorders, infections and skin and subcutaneous tissue disorders, while neoplasms and cardiovascular events did not reach significance at the SOC level but were observed at the PT level, including signals for breast cancer, skin cancer, peripheral venous disease, and hypertension. Several factors may explain the differences observed between our findings and those reported in previous studies. Firstly, our analysis relied on FAERS database, which predominantly captures reports from US patients, whereas some studies drew upon randomized clinical trials or global pharmacovigilance databases such as VigiBase. Differences in genetic background, comorbidities, and concomitant medications across populations are well-recognized determinants of AE distributions (58). Secondly, our study was restricted to psoriasis and PsA, whereas other studies may have examined different indications, such as rheumatoid arthritis, or may not have been limited to a specific indication (14, 48). Given the variation in underlying disease mechanisms, immune system alterations, and background therapies, the AE patterns may understandably differ across indications. Finally, even within the JAK inhibitor class, differences in kinase selectivity and binding affinity may result in heterogeneous safety profiles (59).

Among the three investigated drugs, the number of reports from female patients was significantly greater than that from male patients, potentially attributable to higher willingness to participate in pharmacovigilance systems (60) or a higher incidence rate of female patients. In this study, female patients taking tofacitinib exhibited a higher likelihood of developing skin and subcutaneous tissue disorders, which may be linked to sex-related differences in drug metabolism, immune responses, and social behaviors (41). Such sex differences highlighted the importance of considering sex-specific factors when managing and monitoring AEs in patients with psoriasis and PsA. The opposite conclusions in this study regarding the likelihood of gastrointestinal disorders in different age groups for deucravacitinib and tofacitinib may be attributed to differences in indication proportions and drug mechanisms. However, our sensitivity analysis suggested that sex and age had minimal influence on the positive signals for the remaining AEs. Real world studies remain necessary to further elucidate potential age and sex differences. In the sensitivity analysis stratified by reporting country, we observed notable differences in positive AE signals between US and non-US countries reports. Given that FAERS is a US-centric database with the majority of reports originating from the US, these findings suggest that our results may be more representative of the US population.

The analysis of the occurrence time of AEs indicated that most AEs of deucravacitinib occurred within one month and it was essential to conduct monitoring in the early stage of treatment. In contrast, the median occurrence time of AEs for upadacitinib and tofacitinib was around 130 days, which suggested that long-term attention should be paid to their adverse symptoms after medication. In interpreting the results of this study, it is important to consider potential biases arising from differences in both market duration and patient exposure among the three JAK inhibitors. To address this, we calculated annualized reporting rates (reports per 100 person-years) and applied statistical shrinkage in our disproportionality analyses (ROR and IC), which help mitigate these biases and reduce this limitation. Notably, our study revealed a substantial proportion of missing age data. As presented in Table 1 , the extent of missing age data varied considerably across the three JAK inhibitors, with upadacitinib showing the highest rate of missingness (52.53%), followed by deucravacitinib (23.83%) and tofacitinib (10.14%). We acknowledge that the missing age data constitutes a potential source of selection bias. Prospective studies with more comprehensive clinical data will be essential to validate these results in the future. Other factors that should be considered included the relatively high proportion of non-medical professionals in the reports of upadacitinib, which was consistent with the results of other studies (14, 41) Although reports from healthcare providers may be more systematic and detailed, spontaneous reports from consumers often capture a wider range of patient experiences (31). Nevertheless, we must still give consideration to the AEs reported by consumers.

Some limitations of this research should be acknowledged. Firstly, the disproportionality analysis applied in pharmacovigilance study has issues such as lack of detailed patient exposure information, reporting biases, and confounding biases. It cannot provide the true incidence rate and make causal inferences. Hypotheses generated from this analysis require validation in subsequent real-world studies (61). To minimize bias, this study employed statistical shrinkage transformation as a corrective methodology. Secondly, the FAERS database has defects including data quality issues, incomplete clinical data, underreporting data, redundancy and missing information, lack of exposure denominators, and diverse information sources. We strive to ensure data integrity and reliability by removing duplicate data and missing values, as well as performing data extraction and preprocessing in this study. Nevertheless, important clinical variables such as comorbidities, concomitant medications, laboratory parameters and other clinical details are often incomplete and not systematically or consistently captured, which limits our ability to fully adjust for these potential confounders. Thirdly, this study relied solely on the FAERS database, which is a spontaneous reporting system primarily comprising data from the US. Consequently, the demographic homogeneity restricts the ability to fully assess the influence of racial, genetic, and regional factors on the safety profiles of JAK inhibitors. Future studies that incorporate multinational or multiethnic databases and leverage real-world data with richer clinical details are warranted. Such studies would help validate and extend these findings across diverse populations and comprehensively evaluate the influence of comorbidities and other clinical factors. Despite these limitations, this study still makes use of a large real-world database, providing valuable insights for the detection of AEs.

This systematic pharmacovigilance study reveals distinct AE profiles associated with JAK inhibitor use in psoriasis and PsA patients. Skin and subcutaneous tissue disorders, infections and infestations, and gastrointestinal disorders were frequently reported AE signals for JAK inhibitors. Musculoskeletal and connective tissue disorders were prominent AEs associated with upadacitinib and tofacitinib. The reporting rates of skin and subcutaneous tissue disorder AEs for deucravacitinib were higher than those for upadacitinib and tofacitinib, whereas most other AE reporting rates for deucravacitinib were lower. The unexpected PT signals related to musculoskeletal and connective tissue disorders of deucravacitinib, as well as the PT signals related to nervous system disorders and psychiatric disorders of upadacitinib, required heightened attention. Comparisons between psoriasis and PsA showed broadly consistent AE signal patterns. Subgroup analysis suggested that female subjects had a higher likelihood of developing skin and subcutaneous tissue disorders after taking tofacitinib. Since disproportionality analysis cannot infer causal relationships, the results require further validation in studies with denominator data. Clinicians should maintain heightened vigilance for potential AEs and implement enhanced patient monitoring protocols to optimize medication safety.