Background: Psoriasis is a chronic immune-mediated inflammatory disease that significantly impairs quality of life and requires long-term management. Biologic therapies targeting cytokines such as TNF-α, IL-12/23, and IL-17 have revolutionized treatment. However, concerns remain regarding their long-term efficacy and safety, particularly for rare adverse events and sustained clinical response.

Objective: To evaluate and compare the long-term efficacy and safety of biologic therapies—specifically anti-TNF-α and IL-12/23 inhibitors—in patients with moderate to severe psoriasis.

Methods: An observational systematic review and meta-analysis was conducted including cohort and case-control studies of adult patients treated for ≥1 year. Databases including PubMed, Web of Science, and Google Scholar were searched. Primary outcomes included PASI 75 response rates and serious adverse events (infections, malignancy, and major adverse cardiovascular events). Statistical analysis was performed using a random-effects model.

Results: IL-12/23 inhibitors demonstrated higher efficacy than anti-TNF-α agents, achieving PASI 75 in 84% vs. 76.18% at year 1. Long-term response with IL-12/23 inhibitors remained stable (~80–91%). Rates of serious infections (2.4% vs. 2.9%) and malignancy (3.9% vs. 3.7%) were comparable between groups. IL-12/23 inhibitors showed lower rates of common adverse events (9.22%) compared to anti-TNF-α (25.77%). No significant differences were observed in major cardiovascular events. 

Conclusions: IL-12/23 inhibitors provide superior efficacy with a favorable safety profile compared to anti-TNF-α therapies. Both classes show similar risks for serious adverse events, but anti-TNF-α agents are associated with higher rates of common side effects.

Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting approximately 2% of the global population and significantly impairing patients’ quality of life. It is characterized by complex interactions between immune cells, cytokines, and keratinocytes, with key roles played by TNF-α, IL-12/23, and IL-17 pathways. Although multiple therapeutic options exist, including topical, systemic, and phototherapy modalities, biologic therapies have revolutionized the management of moderate to severe psoriasis by targeting specific immunological pathways with high efficacy [1-3]. 

Despite the proven short-term efficacy of biologics in randomized controlled trials (RCTs), most available evidence is limited by relatively short follow-up durations, often insufficient to evaluate sustained efficacy and rare but serious adverse events such as malignancy, serious infections, and cardiovascular complications [4]. Additionally, head-to-head comparisons between biologic classes are scarce, and long-term real-world effectiveness data remain limited. This creates uncertainty in determining the optimal therapeutic strategy for long-term disease control [5-7]. 

To address this gap, observational meta-analysis provides a valuable approach by incorporating real-world data and longer follow-up periods, allowing for better assessment of long-term outcomes and safety profiles. Unlike traditional RCT-based analyses, this study integrates evidence from observational studies to capture clinically relevant endpoints over extended durations, thereby offering a more comprehensive evaluation of biologic therapies in routine practice [8-11]. 

Given the growing use of biologics and the need for individualized treatment strategies, it is essential to clarify their long-term benefit–risk profile. Clinicians require robust comparative data to guide therapeutic decisions, particularly when balancing efficacy with safety concerns in chronic lifelong treatment.

Therefore, this study aimed to compare the long-term efficacy and safety of biologic therapies—specifically anti-TNF-α and IL-12/23 inhibitors—in patients with moderate to severe psoriasis, in order to better define their therapeutic profiles and support evidence-based clinical decision-making.

Study Design

This systematic review and observational meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The study aimed to evaluate the long-term efficacy and safety of biologic therapies in patients with moderate to severe psoriasis.

Search Strategy

A comprehensive literature search was performed in January 2023 using PubMed, Web of Science, and Google Scholar databases up to September 2022. The search strategy included combinations of keywords related to psoriasis and biologic therapies such as “psoriasis,” “psoriatic arthritis,” “etanercept,” “infliximab,” “adalimumab,” “ustekinumab,” “secukinumab,” as well as conventional therapies including “methotrexate,” “cyclosporine,” and “acitretin.” Observational studies were specifically filtered, and no language restrictions were applied. Additionally, reference lists of relevant reviews were screened to identify further eligible studies.

Screening Process

After the databases were searched, we removed duplicates from the returned articles using EndNote version 7 [12]. In order to start the screening process, we then moved the remaining articles to Rayyan software [13]. In order to decide which papers should be included, two writers independently examined the titles and abstracts of the included papers. The full texts of the included articles from the earlier phase were then screened. Any differences of opinion were resolved by consensus or by referring them to a senior author. The study selection process was illustrated using a PRISMA flow diagram.

Eligibility Criteria (PICOS Framework)

We conducted a systematic search of the literature according to the PICOS model (Population, Intervention, Comparison, Outcomes, Study design):

•               Population: Adult patients (≥18 years) diagnosed with moderate to severe psoriasis, with or without psoriatic arthritis. 

•               Intervention: Biologic therapies including anti-TNF-α agents (etanercept, infliximab, adalimumab), IL-12/23 inhibitors (ustekinumab), and IL-17 inhibitors (secukinumab). 

•               Comparison: Other biologic classes or conventional systemic therapies such as methotrexate, cyclosporine, and systemic retinoids. 

•               Outcomes:

o              Primary outcomes included PASI 75 response and serious adverse events (serious infections, malignancy, and major adverse cardiovascular events). 

o              Secondary outcomes included Physician Global Assessment (PGA) score (0 or 1) and overall adverse events. 

•               Study Design: Observational studies, including cohort and case-control studies, with a minimum follow-up duration of one year. 

Inclusion and Exclusion Criteria

Studies were included if they were observational in design and evaluated the efficacy and/or safety of biologic therapies in psoriasis patients over at least one year. Studies involving adults treated with monotherapy of biologic or conventional agents were considered eligible.

Studies were excluded if they involved biologics not specified in the protocol (e.g., brodalumab, ixekizumab, tildrakizumab, guselkumab), included irrelevant treatment arms, or were non-original articles such as reviews or conference abstracts without sufficient data.

Data extraction was performed independently by two reviewers using standardized data collection forms. Extracted data included study characteristics (author, publication year, study design), patient demographics (sample size, age, gender distribution, comorbidities), and clinical outcomes (PASI 75 achievement, serious infections, malignancy, MACEs, and common adverse events). Any discrepancies were resolved through consensus. When necessary, attempts were made to contact study authors via email to obtain missing or unclear data.

Risk of Bias Assessment

The methodological quality of included studies was assessed using a modified Downs and Black checklist. This tool evaluated study quality across multiple domains, including participant selection, confounding factors, exposure measurement, outcome assessment, completeness of data, and reporting bias. Each study was categorized based on its overall risk of bias.

Table 1: Summarized the specific items of the Downs and Black checklist for each included study.

Assessment of Heterogeneity and Publication Bias

Statistical heterogeneity among studies was assessed using Cochran’s Q test and the I² statistic. Publication bias was planned to be evaluated using funnel plots and statistical tests such as Begg’s and Egger’s tests when at least ten studies were available. However, this analysis was not performed due to the limited number of included studies.

Data synthesis was performed using a random-effects model to account for between-study variability. Results were reported as pooled proportions or odds ratios (ORs) with corresponding 95% confidence intervals (CIs). All statistical analyses were conducted using MedCalc software (version 20.104, Ostend, Belgium).

Study Selection

A total of 726 records were initially identified through the database search. After removing duplicate entries, two independent reviewers screened the titles and abstracts to exclude studies that were not relevant. Subsequently, full-text articles of the remaining studies were assessed by all authors to determine eligibility. In cases of disagreement, a third reviewer was consulted to reach a final decision. When necessary, corresponding authors of the included studies were contacted to clarify missing or unclear information. A detailed list of excluded studies, along with the reasons for exclusion, was documented. The overall study selection process was illustrated using a flow diagram (Figure 1).

Figure 1: PRISMA flow chart outlining the process of study selection.

1. PASI 75 Response at Year 1

Two studies assessed PASI 75 outcomes at one year for anti-TNF-α therapies, including a total of 472 patients, while four studies evaluated IL-12/23 inhibitors with a combined sample size of 592 patients. The analysis demonstrated that IL-12/23 inhibitors were more effective in achieving PASI 75 compared to anti-TNF-α agents. The pooled response rate was 84% (95% CI: 77.9–89.3) for IL-12/23 inhibitors, whereas it was 76.18% (95% CI: 69–82.6) for anti-TNF-α therapies (Figure. 2).

2. PASI 75 Response at Years 2, 3, 4, and 5

Long-term PASI 75 outcomes beyond the first year were reported exclusively for IL-12/23 inhibitors. Specifically, four studies provided data for years 2 and 3, while three studies reported outcomes for years 4 and 5. The pooled PASI 75 response rates were 80.1% (95% CI: 74.6–84.2) at year 2, 80.1% (95% CI: 75.56–84.2) at year 3, 91% (95% CI: 72.68–99.6) at year 4, and 81% (95% CI: 74.8–86.5) at year 5 (Figure. 3–6).

3. Rate of Serious Infections

Five studies involving 3,901 patients treated with anti-TNF-α agents reported a pooled serious infection rate of 2.9% (95% CI: 2.4–3.5) (Fig. 7A). In contrast, two studies including 805 patients treated with IL-12/23 inhibitors showed a pooled rate of 2.4% (95% CI: 0.04–8) (Figure. 7B).

Additionally, five comparative studies evaluated the risk of serious infections between the two treatment groups, yielding an odds ratio of 1.06 (95% CI: 0.8–1.5), indicating no statistically significant difference (Figure. 8).

4. Rate of Malignancy

Seven studies with a total of 6,379 patients receiving anti-TNF-α therapies reported a malignancy rate of 3.7% (95% CI: 1.9–6) (Fig. 9A). Meanwhile, two studies including 805 patients treated with IL-12/23 inhibitors demonstrated a malignancy rate of 3.9% (95% CI: 2.7–5.4) (Figure. 9B).

Four studies comparing malignancy risk between both groups produced an odds ratio of 1.3 (95% CI: 0.88–1.96), suggesting no significant difference (Figure. 10).

5. Rate of Major Adverse Cardiovascular Events (MACEs)

Five studies involving 3,901 patients receiving anti-TNF-α therapies reported a MACE rate of 1.8% (95% CI: 0.8–3.25) (Fig. 11A). In comparison, three studies including 1,183 patients treated with IL-12/23 inhibitors showed a rate of 1.18% (95% CI: 0.64–1.8) (Figure. 11B).

Across five comparative studies, the calculated odds ratio for MACEs between the two groups was 1.003 (95% CI: 0.64–1.55), indicating no statistically significant difference (Figure. 12).

Rate of Common Adverse Events

Six studies with a total sample size of 4,165 patients receiving anti-TNF-α therapies reported a pooled rate of common adverse events of 25.77% (95% CI: 15.87–37.12) Figure. 13A). In contrast, three studies including 491 patients treated with IL-12/23 inhibitors demonstrated a lower rate of 9.22% (95% CI: 4.55–15.3) (Fig. 13B).

Furthermore, four studies comparing both groups yielded an odds ratio of 2.006 (95% CI: 0.47–8.43), indicating a higher, though not statistically significant, frequency of common adverse events in patients receiving anti-TNF-α therapies (Figure. 14).

Table 2: Characteristics of one arm included studies

Table 3: Characteristics of two arm included studies

Figure 2: Forest plot for Rate of PASI 75 at year 1. (A) anti-TNF-α. (B) IL-12/23 Inhibitors

Figure 3: Forest plot for Rate of PASI 75 at year 2 with IL-12/23 Inhibitors

Figure 4: Forest plot for Rate of PASI 75 at year 3 with IL-12/23 Inhibitors

Figure 5: Forest plot for Rate of PASI 75 at year 4 with IL-12/23 Inhibitors

Figure 6: Forest plot for rate of PASI 75 at year 5 with IL-12/23 Inhibitors.

Figure 7A: Forest plot for rate of serious infection with anti-TNF-α.

Figure 7B: Forest plot for Rate of PASI 75 at year 4 with IL-12/23 Inhibitors

Figure 8: Forest plot for comparison of anti-TNF-α versus IL-12/23 Inhibitors as regards occurrence of serious infection.

Figure 9A: Forest plot for rate of malignancy with anti-TNF-α.

Figure 9B: Forest plot for rate of malignancy with IL-12/23 Inhibitors.

Figure 10: Forest plot for comparison of anti-TNF-α versus IL-12/23 Inhibitors as regards occurrence of malignancy.

Figure 11A: Forest plot for rate of MACE with anti-TNF-α.

Figure 11B: Forest plot for rate of MACE with IL-12/23 Inhibitors.

Figure 12: Forest plot for comparison of anti-TNF-α versus IL-12/23 Inhibitors as regards occurrence of MACE.

Figure 13A: Forest plot for rate of common adverse effects with anti-TNF-α.

Figure 13B: Forest plot for rate of common adverse events with IL-12/23 Inhibitors.

Figure 14: Forest plot for comparison of anti-TNF-α versus IL-12/23 Inhibitors as regards occurrence of common adverse events.

Psoriasis is a chronic, immune-mediated inflammatory skin disorder in which dysregulation of key cytokines—namely tumor necrosis factor-alpha (TNF-α), interleukin (IL)-23, and IL-17—plays a fundamental role in disease pathogenesis. Targeted biologic therapies directed against these cytokines have significantly improved disease control, particularly in moderate to severe cases. However, while these agents demonstrate strong short-term efficacy, evidence suggests that their effectiveness may diminish over prolonged treatment durations (35). In light of this, the present study was conducted to evaluate and compare the long-term efficacy and safety profiles of anti-TNF-α agents and IL-12/23 inhibitors.

Regarding Efficacy Outcomes (PASI 75 Response), the findings of this study indicate that IL-12/23 inhibitors provide superior efficacy compared to anti-TNF-α therapies at one year, with pooled PASI 75 response rates of 84% and 76.18%, respectively. These results are consistent with those reported by Sawyer et al. (36), who conducted a network meta-analysis of biologic therapies and demonstrated that IL-12/23 inhibition (particularly ustekinumab) achieved better PASI outcomes than anti-TNF agents such as infliximab, adalimumab, and etanercept at approximately 52 weeks.

Similarly, multiple network meta-analyses (37-39) have reported that IL-12/23 inhibitors generally outperform anti-TNF-α agents in achieving PASI 75 responses, although infliximab has occasionally demonstrated superior efficacy compared to other biologics. It is important to emphasize that these analyses were largely based on short-term data (12–24 weeks), which limits their applicability to long-term treatment outcomes.

Reich et al. (40) further supported these findings by demonstrating that IL-12/23 inhibitors achieved higher PASI 50, 75, and 90 response rates than anti-TNF therapies, again with infliximab being a notable exception. Armstrong et al. (41) also reported similar trends, showing that IL-12/23 inhibitors were superior in achieving PASI 90 in short-term analyses (10–16 weeks) and PASI 100 in longer-term outcomes (48–52 weeks). In contrast, Mahil et al. (42) reported differing results, suggesting that anti-TNF-α agents—particularly infliximab and adalimumab—may demonstrate greater efficacy in short-term settings, highlighting variability across studies.

With respect to long-term outcomes, this study revealed a lack of sufficient data evaluating PASI 75 responses beyond one year for anti-TNF therapies. Conversely, IL-12/23 inhibitors demonstrated sustained efficacy over extended follow-up periods, maintaining PASI 75 response rates of approximately 80% at years 2, 3, and 5, and reaching up to 91% at year 4, although with overlapping confidence intervals.

Regarding Serious Infections, the analysis showed that the incidence of serious infections was comparable between anti-TNF-α agents (2.9%) and IL-12/23 inhibitors (2.4%), with no statistically significant difference (OR ≈ 1.06). These findings are consistent with those of Feng et al. (43), who reported no increased risk of serious infections across biologic classes in randomized controlled trials involving adult psoriasis patients.

However, subgroup analyses from the same study indicated a potential increase in infection risk with IL-12/23 inhibitors compared to anti-TNF agents (OR 1.67), although this finding may be limited by the relatively short duration of included trials (12–52 weeks). Similarly, Yiu et al. (29) reported increased risks of serious infections with certain anti-TNF agents (adalimumab and infliximab), while IL-12/23 inhibitors did not show a statistically significant increase in infection risk.

In contrast, Meng et al. (44) found no difference in serious infection rates between IL-12/23 inhibitors and placebo over both short-term and long-term follow-up periods. The discrepancy between these findings and those of Dommasch et al. (45), who reported no increased infection risk with anti-TNF therapies, may be attributed to differences in study design and follow-up duration, as shorter placebo-controlled trials may underestimate long-term adverse events.

Regarding Malignancy Risk, the incidence of malignancy was similar between anti-TNF-α (3.7%) and IL-12/23 inhibitor groups (3.9%), with no significant difference observed (OR ≈ 1.3). These findings are consistent with Dommasch et al. (45), who conducted a meta-analysis of RCTs and reported a comparable risk of malignancy among patients receiving anti-TNF therapy.

Additionally, Hong et al. (46), in a large nationwide cohort study, found no significant increase in malignancy risk among psoriasis patients treated with biologics (HR 1.24), with similar hazard ratios observed for TNF-α inhibitors (1.19) and IL-12/23 inhibitors (1.30). Although Esse et al. (47) reported a higher relative risk of melanoma with anti-TNF-α therapy (HR 1.57), the overall evidence suggests that biologic therapies are not strongly associated with increased cancer risk.

Furthermore, Garcia-Doval et al. (48) demonstrated that cumulative exposure to biologic therapy was not significantly associated with an increased risk of malignancy (adjusted OR 1.02 per year), reinforcing the long-term safety of these agents.

Regarding Major Adverse Cardiovascular Events (MACEs), the incidence of major adverse cardiovascular events was low in both treatment groups, with rates of 1.18% for IL-12/23 inhibitors and 1.8% for anti-TNF-α agents, indicating no significant difference. These findings are supported by multiple studies, including Champs et al. (49), who found no increased risk of MACEs or congestive heart failure in patients receiving biologics compared to placebo.

Similarly, Nartowicz et al. (50) and Rungapiromnan et al. (51) reported no statistically significant differences in cardiovascular risk among psoriasis patients treated with various biologic agents, further supporting the cardiovascular safety of these therapies.

Regarding Common Adverse Events, a significant difference was observed in the rate of common adverse events, which was substantially higher in patients receiving anti-TNF-α therapies (25.77%) compared to those treated with IL-12/23 inhibitors (9.22%), with an odds ratio of approximately 2.006. These findings are consistent with Xu et al. (52), who reported higher adverse event rates with anti-TNF therapies compared to IL-12/23 inhibitors.

Mahil et al. (42) also found that infliximab was associated with the highest likelihood of adverse events among biologics, while Mourad et al. (53) demonstrated increased adverse event rates in patients receiving anti-TNF agents alone or in combination therapies. Conversely, Bai et al. (54) reported that IL-12/23 inhibitors have a more favorable safety profile, with lower rates of both common and serious adverse events.

However, conflicting evidence exists. Nast et al. [37] reported no significant difference in adverse event rates between anti-TNF therapies and placebo, while Shear et al. [55] found that etanercept was associated with the lowest risk of adverse events among biologics, highlighting ongoing inconsistencies in the literature.

Clinical Implications

The findings of this study provide important insights for clinical decision-making in the management of moderate to severe psoriasis. IL-12/23 inhibitors demonstrated superior and more sustained efficacy compared to anti-TNF-α therapies, along with a lower rate of common adverse events. This suggests that IL-12/23 inhibitors may be preferable as a long-term therapeutic option, particularly in patients requiring prolonged disease control. Additionally, the comparable rates of serious infections, malignancy, and cardiovascular events between the two classes indicate that both therapies have acceptable safety profiles, allowing clinicians to individualize treatment based on patient comorbidities, prior treatment response, and tolerability. The higher rate of common adverse events associated with anti-TNF-α agents should be considered when selecting therapy, especially in patients at risk of poor adherence.

Strength Points

This study has several strengths. First, it utilized observational studies, which are more suitable for evaluating long-term efficacy and safety compared to randomized controlled trials, particularly for detecting rare and delayed adverse events. Second, the inclusion of a large pooled sample size enhanced the statistical power and reliability of the findings. Third, the study focused on prolonged treatment durations, addressing a key limitation in existing literature that predominantly relies on short-term data. Finally, the comparative analysis between biologic classes provides clinically relevant insights that can directly inform therapeutic decisions.

Despite its strengths, this study has several limitations. The included studies exhibited heterogeneity in design, patient populations, and outcome reporting, which may affect the consistency of the results. Additionally, there was a lack of sufficient long-term data for certain biologic classes, particularly anti-TNF-α therapies beyond one year and IL-17 inhibitors overall. The observational nature of the included studies also introduces potential biases, such as confounding factors and selection bias. Furthermore, the absence of randomized head-to-head comparisons limits the ability to draw definitive conclusions regarding superiority between treatments.

IL-12/23 inhibitors demonstrated superior efficacy and a more favorable safety profile compared to anti-TNF-α therapies in the treatment of moderate to severe psoriasis. While both classes showed similar risks for serious adverse events, IL-12/23 inhibitors were associated with lower rates of common adverse events and more sustained long-term effectiveness. These findings support the growing role of IL-12/23 inhibitors as a preferred option for long-term disease management.

Clinicians are encouraged to consider both efficacy and safety profiles when selecting biologic therapies and to adopt individualized treatment strategies tailored to patient characteristics and comorbidities.

Future Perspectives

Future research should focus on long-term, large-scale observational studies and real-world registries to further clarify the durability of biologic therapies and detect rare adverse events. Comparative studies involving newer biologics, particularly IL-17 and IL-23 inhibitors, are needed to provide a more comprehensive understanding of treatment hierarchies. Additionally, personalized medicine approaches incorporating genetic, immunologic, and biomarker profiling may help predict treatment response and optimize therapy selection. Long-term head-to-head trials between biologic classes would also be valuable to strengthen current evidence and guide clinical guidelines.