Safety and efficacy of Deucravacitinib for moderate to severe plaque psoriasis: A meta‐analysis

Abstract

Background

To systematically evaluate the safety and efficacy of Deucravacitinib for moderate to severe plaque psoriasis.

Materials and Methods

Randomized controlled trials (RCTs) of Deucravacitinib for moderate to severe plaque psoriasis in PubMed, Cochrane Library, Embase, and Web of Science were searched from database establishment to April 2023. Literature quality was independently evaluated by two investigators using the Cochrane risk‐of‐bias assessment tool, and the systematic analysis was made using StateSE15 and RevMan 5.3 software.

Results

Four RCTs were included, including 1751 patients with moderate to severe plaque psoriasis. Meta‐analysis showed that the differences in efficacy and adverse events (AEs) between the Deucravacitinib group and placebo group were significant (p < 0.05). The patients in the Deucravacitinib group took orally 3–12 mg daily for 12 sequential weeks or 6 mg daily for 52 sequential weeks. Psoriasis Area and Severity Index (PASI) reduced by 75% (PASI 75), (PASI 90), and (PASI 100), static Physician Global Assessment (sPGA) of 0 or 1 (sPGA 0/1), Dermatology Life Quality Index of 0 or 1 (DLQI 0/1), and Psoriasis Symptoms and Signs Diary (PSSD) were significantly higher in the Deucravacitinib group compared to the placebo group, with significant differences (p < 0.05). The most frequently encountered AEs after treatment in the Deucravacitinib group was nasopharyngitis.

Conclusion

Oral administration of Deucravacitinib is effective for moderate to severe plaque psoriasis. Attention should be paid to the occurrence of AEs, and more RCTs are required to evaluate the relationship between the dose and safety and efficacy.

1. INTRODUCTION

Psoriasis is a frequently encountered refractory chronic inflammatory skin disease in dermatology due to the interaction between the immune system, autoantigens, and multiple environmental factors, which may be induced by such factors as infection, trauma, and environment. At present, the incidence of psoriasis is 2%–3%. ¹ Psoriasis vulgaris or plaque psoriasis accounts for up to 90% of psoriasis patients, featuring well‐demarcated round or oval plaques, with the surface scattered with silver‐white scales. Some of them suffered from moderate to severe plaque psoriasis, which is conventionally treated with systemic therapy (such as acitretin, methotrexate, or cyclosporin) or phototherapy, in addition to topical medication. ² At present, biological products have been widely employed for moderate to severe plaque psoriasis, including tumor necrosis factor (TNF), interleukin (IL), etc. Some psoriasis patients developed such diseases as eczema, atopic dermatitis, or urticaria after the treatment with biological agents, ³ which limited the use of biological agents and hindered some patients with moderate to severe psoriasis from being fully treated. The Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) signaling pathway has a significant impact on the intracellular signal transduction of cytokines in various cellular regulatory processes ⁴ , ⁵ and has been demonstrated effective for patients with moderate to severe psoriasis. Tyrosine kinase 2 (TYK2) is a new intracellular signal transduction enzyme in the JAK family. At present, Deucravacitinib (R&D code: BMS‐986165) developed by Bristol‐Myers Squibb (BMS) is the first‐ever and only selective TYK2 inhibitor that can be taken orally in the world and approved by the FDA on September 9, 2022 for treating adults with moderate to severe plaque psoriasis eligible for undergoing systemic therapy or phototherapy. ⁶ In this study, a meta‐analysis was made on the safety and efficacy of Deucravacitinib and placebo for plaque psoriasis, and the safety and efficacy of Deucravacitinib were further discussed and analyzed to provide a concrete basis for the clinical use of Deucravacitinib.

2. MATERIALS AND METHODS

2.1. General data

The relevant literature was searched through the computer in PubMed, Cochrane Library, Embase, and Web of Science from establishment to April 2023. The search term included psoriasis OR psoriases OR pustulosis of Palms and Soles OR pustulosis palmaris et plantaris OR palmoplantaris Pustulosis OR Pustular Psoriasis of Palms AND deucravacitinib OR BMS‐986165.

2.2. Inclusion and exclusion criteria

Inclusion: (1) Study type: RCTs of Deucravacitinib for plaque psoriasis; (2) Study subject: Patients diagnosed with plaque psoriasis, aged above 18, without limitations on gender; (3) Intervention: The patients in the test group received Deucravacitinib; (4) Outcome indicators: The efficacy indicator was the number of patients with Psoriasis Area and Severity Index (PASI) decreased by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100). The safety indicators were the incidence of adverse events (AEs) and severe AEs (SAEs). Exclusion criteria: (1) Literature without a control group; (2) Duplicately published literature and literature with references designed in a non‐standardized way; (3) Literature not conforming to the intervention; (4) Retrospective study.

2.3. Data extraction

The retrieved literature was preliminarily screened using EndNote20. Then the abstracts and full texts were read in detail to eliminate the unqualified ones. This process was carried out independently by two investigators, and the literature in doubt was submitted to a third investigator for review to determine whether to include it or not.

2.4. Literature quality evaluation

The methodological quality of the included RCTs was assessed using the Cochrane risk‐of‐bias assessment tool based on randomization methods, allocation concealment, blinding of investigators and subjects, blinding of study outcome evaluation, incompleteness of outcome data, selective reporting of study results, and other possible risks of bias. They were determined as low risk (correct method application), unclear risk (unclear description of method application), and high risk (incorrect method application or method unemployed) to determine the overall risk of bias. This process was carried out independently by two investigators, and their results were cross‐checked. In case of any disagreement, a conclusion was drawn through discussion between the two investigators. If no consensus can be reached, a third investigator assisted in it. ⁷

2.5. Statistical methods

Meta‐analysis was carried out using StateSE15 and RevMan5.3 statistical software, and efficacy indicators (PASI 75, PASI 90, PASI 100, static Physician Global Assessment [sPGA] 0/1, Dermatology Life Quality Index of 0 or 1 [DLQI 0/1], and Psoriasis Symptoms and Signs Diary [PSSD]) and safety indicators (incidence of AEs) were included as the measurement data in this study. PSSD score was enumeration data and was statistically analyzed, with risk ratio (RR) and the 95% confidence interval (CI) as the effect size. The I ² test was employed for clinical heterogeneity of included literature. If there was no statistical heterogeneity among studies (I ² < 50%, p > 0.05), a fixed effects model (FEM) was employed for meta‐analysis; if there was statistical heterogeneity among studies (I ² ≥ 50%, p ≤ 0.05), a random effects model (REM) was employed. Publication bias was analyzed using Egger's test. p < 0.05 was considered significant.

3. RESULTS

3.1. Literature screening process and basic properties of included studies

Four hundred fifteen articles were obtained from the search, of which 14 articles on treating psoriasis with Deucravacitinib were screened by deleting duplicate published ones and reading their titles and abstracts. Four RCTs ⁸ , ⁹ , ¹⁰ , ¹¹ were finally included, all of which were in English, including 1751 patients, with 1211 in the test group and 540 in the control group. The specific screening process is shown in Figure 1. The basic characteristics of the included studies are shown in Table 1.

FIGURE 1.

PRISMA Process (PRISMA = Preferred Reporting Items for Systematic Review and Meta‐Analysis).

TABLE 1.

Basic properties of included studies.

				Sample size		Gender (M/F)	Mean (years)	age	Intervention		Follow‐up (week)	Outcome
Study	Year	Country	Diagnosis	EG	CG		EG	CG	EG	CG
Papp	2018	Canada	Moderate to severe plaque psoriasis	222	45	194/73	41–47	46	B(3 m/other day; 3 mg/daily; 3 mg twice/daily; 6 mg twice/daily; 12 mg/daily	Placebo	12	F1: F2; F3; F4; F5; F6; F7
NCT04167462	2019		Moderate to severe plaque psoriasis	146	74	180/40	40.3	41.2	B;6 mg/daily	Placebo	52	F2; F3; F4; F5; F6; F7; F8; F9
Armstrong	2023	California	Moderate to severe plaque psoriasis	332	166	343/155	29.6	31.5	B;6 mg/daily	Placebo	52	F2; F3; F4; F5; F6; F7; F8; F9
Strober	2022	USA	Moderate to severe plaque psoriasis	511	255				B:6 mg/once daily	Placebo	52	F2; F3; F4; F5;F6; F7; F8; F9

Note: B: BMS‐986165; F1: PASI50; F2: PASI75; F3: PASI90; F4:PASI100; F5: sPGA0/1; F6: DLQI 0/1; F7: adverse events; F8: PSSD; F9: PSSD score.

Abbreviations: EG, experimental group; CG, control group.

3.2. Quality evaluation results of included literature

All the included studies were randomized controlled double‐blind trials. Random sequence generation was not specifically described in all included literature; allocation concealment was considered low‐risk in three studies and unclear in one; the patient's withdrawal and loss to follow‐up were analyzed in three articles; the participants and personnel blinding, outcome assessment blinding, incomplete outcome data and selective reporting were considered low‐risk in the four studies (Figure 2).

FIGURE 2.

Literature quality evaluation.

3.3. The efficacy of Deucravacitinib versus placebo for moderate to severe plaque psoriasis

PASI 75, PASI 90, PASI 100, sPGA 0/1, DLQI 0/1, and AEs of Deucravacitinib versus placebo for moderate to severe plaque psoriasis were reported in all four included RCTs, PASI 50 in one RCT, and PSSD and PSSD in three RCTs. There were 1211 patients in the test group (Deucravacitinib) and 540 in the placebo group. The heterogeneity test showed PASI 75 (I ² = 25.8%, p > 0.05), PASI 90 (I ² = 0%, p > 0.05), PASI 100 (I ² = 0%, p > 0.05), sPGA 0/1 (I ² = 0%, p > 0.05), DLQI 0/1 (I ² = 16.5%, p > 0.05), and PSSD (I ² = 0%, p > 0.05). The meta‐analysis results showed PASI 75 (RR = 5.95, 95%CI [4.70–7.52]), PASI 90 (RR = 11.11, 95%CI [7.15–17.24]), PASI 100 (RR = 12.09, 95%CI [5.51–26.54]), sPGA 0/1 (RR = 6.94, 95%CI [5.34–9.03]), DLQI 0/1 (RR = 4.42, 95%CI [3.44–5.68]), and PSSD (RR = 6.66, 95%CI [2.70–16.43]). Since there was no heterogeneity in the above indicators, a FEM was employed. Due to the presence of heterogeneity in PSSD score (I ² = 66.8%, p < 0.05), a REM was employed. The meta‐analysis results showed the PSSD score (RR = −0.92, 95% CI [−1.04 to −0.81]). The above indicators were significantly better in the test group than in the placebo group, and the difference was significant (p < 0.05) (Figures 3, 4, 5, 6, 7, 8, 9).

FIGURE 3.

Forest plot for meta‐analysis of PASI 75 in both groups.

FIGURE 4.

Forest plot for meta‐analysis of PASI 90 in both groups.

FIGURE 5.

Forest plot for meta‐analysis of PASI 100 in both groups.

FIGURE 6.

Forest plot for meta‐analysis of sPGA 0/1 in both groups.

FIGURE 7.

Forest plot for meta‐analysis of DLQI 0/1 in both groups.

FIGURE 8.

Forest plot for meta‐analysis of PSSD in both groups.

FIGURE 9.

Forest plot for meta‐analysis of PSSD score in both groups.

3.4. Safety evaluation

Heterogeneity analysis of the incidence of AEs and SAEs in the included studies showed that there was a certain heterogeneity in AEs (I ² = 62.5%, p < 0.05), so a REM was employed; no heterogeneity in SAEs (I ² = 0%, p > 0.05), so a FEM was employed. There was no significant difference in the incidence of AEs (RR = 1.16, 95% CI [0.98–1.37]) and SAEs (RR = 0.64, 95% CI [0.36–1.16]) between the test and placebo groups, and the results were not significant (p > 0.05) (Figures 10 and 11).

FIGURE 10.

Forest plot for meta‐analysis of AEs in both groups.

FIGURE 11.

Forest plot of meta‐analysis of SAEs in both groups.

The most frequently encountered AE of Deucravacitinib for moderate to severe plaque psoriasis is nasopharyngitis, followed by upper respiratory tract infection, headache, and diarrhea. There were two patients with pericarditis, three with gastroenteritis, and two with cholecystitis.

3.5. Publication bias and sensitivity analysis

PASI 75, PASI 90, PASI 100, SPGA 0/1, DLQI 0/1, AEs, and SAEs were mentioned in all four eligible studies, while PSSD and PSSD scores were discussed in three studies. Egger's test results showed PASI 75 (p = 0.518), PASI 90 (p = 0.383), PASI 100 (p = 0.892), SPGA 0/1 (p = 0.431), DLQI 0/1 (p = 0.101), AEs (p = 0.765), SAEs (p = 0.612), PSSD (p = 0.948), and PSSD score (p = 0.511), indicating a small possibility of publication bias (Figures S1–S9). There was substantial heterogeneity in AEs and PSSD score, and sensitivity analysis showed low sensitivity, indicating that the meta‐analysis results were stable (Figures S10 and S11).

4. DISCUSSION

The JAK‐STAT signaling pathway has a significant impact on the intracellular signal transduction of cytokines in many cellular regulatory processes, ⁴ , ¹² and JAK 1/2/3 inhibitors have been proven to be effective in blocking the JAK‐STAT pathway in patients with moderate to severe psoriasis. However, the relative nonspecificity and low therapeutic index of the existing JAK inhibitors were still challenging. ¹² , ¹³

TYK2 is a member of the JAK family, which includes JAK1, JAK2, and JAK3. JAK is of vital importance in mediating the signal transduction of various cytokines that may induce inflammation. Currently, studies show that TYK2 has a significant impact on the differentiation and immune response of innate immune cells by modulating the mediation of type I IFN, IL‐12, IL‐23, IL‐10, and IL‐6, and participating in regulating multiple important targets in the pathogenesis of psoriasis. ¹⁴ , ¹⁵ The above cytokine pathways participate in immune‐mediated disease‐related pathological processes, which may contribute to the activation and hyperproliferation of keratinocytes, leading to the formation of characteristic plaques. This has a large share in the pathogenesis of psoriasis. A genome‐wide association study (GWAS) carried out in 2016 shows that TYK2 transduces downstream signals of type I IFN, gp130, IL‐10R2, IL‐13Ra, and IL‐12Rb1 cytokine receptors, so the TYK2 gene is associated with a number of autoimmune diseases. Since the pathogenesis of psoriasis is associated with the cytokine signal transduction pathway, deleting the TYK2 gene is associated with susceptibility to psoriasis. ¹⁶ Different from traditional JAK inhibitors, Deucravacitinib has a unique mechanism of action and is a selective TYK2 allosteric inhibitor, with high affinity to TYK2 pseudokinase domain Janus homology 2 (JH2) (IC50 = 0.2 nmol/L), and high selectivity of Janus homology 1 (JH1) in the JAK family (IC50 > 10 000 nmol/L). ¹⁷ Deucravacitinib inhibited TYK2‐mediated phosphorylation of STAT1 and STAT3 in IFN‐α‐ and IL‐23‐induced human peripheral blood mononuclear cells, respectively. ¹⁸ However, the inhibiting effect on receptor‐mediated pathways relying on other JAKs is greatly reduced by more than 100 times, which can reduce the risk of serious infection, anemia, neutropenia, dyslipidemia, and other AEs due to the inhibition of JAKs 1–3. ¹⁹

The study results showed that the efficacy indicators of PASI 75, PASI 90, PASI 100, SPGA 0/1, DLQI 0/1, PSSD, and PSSD score in the test group were significantly higher than those in the placebo group. The meta‐analysis results of safety indicators showed that the differences in the incidence of AEs and SAEs were not significant between the test and placebo groups (p > 0.05). It was reported in one study carried out by Strober et al. ⁸ that a 75‐year‐old female in the test group died 9 days after drug withdrawal due to heart failure and sepsis. The female had obesity, rheumatoid arthritis, hypertension, stroke, and cardiac pacemaker implantation in the past, and was hospitalized for multiple cardiac arrests on the day before death. Her death was considered unrelated to Deucravacitinib. Furthermore, in their study, a 57‐year‐old Asian male with a history of type 2 diabetes, hepatitis C, cirrhosis, and smoking died of hepatocellular carcinoma on day 298, which was also considered unrelated to Deucravacitinib. Our study demonstrated good safety and efficacy of Deucravacitinib for psoriasis, while its long‐term safety and efficacy need to be further verified by clinical trials with a long course of treatment. The analysis results of publication bias in this study showed no significant difference in the publication bias results of outcome indicators, indicating a small possibility of bias and similar quality of included articles. At present, there is no relevant meta‐analysis of the safety and efficacy of Deucravacitinib versus placebo for moderate to severe plaque psoriasis.

Four RCTs ⁸ , ⁹ , ¹⁰ , ¹¹ were included in this systematic evaluation, of which three articles were scored highly in quality, ⁸ , ⁹ , ¹⁰ with high representativeness, and another article was an NCT study. ¹¹ The doses of administration included 3, 6, and 12 mg, and the drug was administered orally. The efficacy and AEs in patients were observed in one study at Week 12, ¹⁰ and the follow‐up period of the other three studies was 52 weeks. ⁸ , ⁹ , ¹¹ Inclusion and exclusion criteria were clearly defined, and the efficacy of PASI, sPGA 0/1, DLQI 0/1, and PSSD was determined according to the same criteria. Since PASI 50 was only analyzed in one RCT, PASI 50 was not analyzed in this meta‐analysis. Deucravacitinib was put on the market for a short time, and the quantity of literature included was small, which hinders the reliability of meta‐analysis results. Sustained attention will be paid to relevant studies in the future to continuously update the results, thus delivering more accurate study results.

5. CONCLUSION

In conclusion, compared to the placebo, Deucravacitinib is effective in treating moderate to severe plaque psoriasis, without significant difference in the risk of AEs, providing a new option for psoriasis patients. Oral administration of this drug excels in improving clinical treatment. Nevertheless, more convincing clinical investigations are required to confirm its long‐term efficacy, the maintenance of clinical efficacy after drug withdrawal, the comparison with the efficacy of biological agents, etc.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Supporting information

Supporting Information

Hu C, Han X, Cui Y, Zhang Y, Cheng Y. Safety and efficacy of Deucravacitinib for moderate to severe plaque psoriasis: A meta‐analysis. Skin Res Technol. 2024;30:e13855. 10.1111/srt.13855

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.