Abstract
Background
Biologics have revolutionized psoriasis treatment; however, relapse of psoriasis after discontinuation of biologics remains unresolved.
Objective
To assess the impact of adjunctive Chinese medicine (CM) therapy on relapse of psoriasis vulgaris (PV) after discontinuation of biologics.
Methods
We constructed a prospective cohort study through a psoriasis case registry platform that enrolled patients treated with biologics (in combination with or without CM). The endpoint event was relapse, defined as loss of psoriasis area and severity index (PASI) 75.
Results
A total of 391 patients completed the study and were included in the analysis, of whom 169 (43.2%) experienced relapse during follow-up. To minimize the bias, a 1:1 propensity score matching (PSM) was performed, generating matched cohorts of 156 individuals per group. Adjuvant CM therapy significantly associated with reduced incidence of relapse (HR =0.418, 95% CI = 0.289 ∼ 0.604, p < 0.001), and the protective effect of CM in the subgroup analysis was significant. In addition, PASI 90 response and disease duration were associated with relapse (p < 0.05).
Conclusion
Adjunctive CM therapy is associated with reduced relapse incidence in PV after discontinuation of biologics.
Introduction
Psoriasis, a chronic, inflammatory, systemic disease characterized by erythematous scales, affects approximately 125 million people worldwide, and it imposes a heavy psychological, physical, and financial burden on sufferers (Citation1–3). Over the past two decades, a new phase in the treatment of psoriasis has occurred as a result of the clinical use of biologics. Biologics are recommended as one of the first-line treatment options for moderate-to-severe psoriasis owing to their efficacy in eliminating psoriatic lesions and their benefits for psoriasis comorbidity and quality of life (Citation4–6).
However, there are still some drawbacks to biologics for psoriasis, and patients frequently experience relapses after treatment discontinuation (Citation7). Previous studies have shown that more than half of patients experience relapse within six months of discontinuation (Citation8), and that the time to relapse decreases as the number of previous biologic treatments increases (Citation9). Given this clinical reality, biologics are recommended for long-term maintenance therapy (Citation10). Nonetheless, treatment interruptions are common among patients with psoriasis in remission due to the secondary loss of efficacy, heavy economic burden, and concerns regarding the safety of long-term treatment (Citation11,Citation12).
Chinese medicine (CM) is an effective treatment for psoriasis and is widely used in Asian populations (Citation13,Citation14). Concerns are growing about whether CM can reduce psoriasis relapse (Citation15). In a small pilot trial, patients treated with CM in combination with topical sequential therapy showed a lower relapse rate compared to those in the topical therapy group (Citation16). The potential of CM to reduce relapse has also been demonstrated in animal experiments. Dihydroartemisinin, a key component of Chinese medicines, has been proven to reduce the severity of psoriasis-like dermatitis in mice after re-stimulation with imiquimod and to inhibit CD8+ circulating memory T (TCM) cells and CD103+ Tissue-resident memory T (TRM) cells in the skin (Citation17). Therefore, adjunctive CM therapy may reduce psoriasis relapse after discontinuation of biologics, but there is a lack of studies to confirm this.
This study was conducted with the help of a registry system and a matched cohort of psoriasis vulgaris (PV) was obtained by propensity score matching (PSM). In this study, we evaluated the effect of adjunctive CM therapy on relapse after discontinuation of biologics in patients with moderate-to-severe PV and analyzed the potential risk factors for relapse, intending to provide new ideas and references for the treatment of psoriasis in the era of biologics.
Methods
Study design and participants
The ‘Psoriasis Case Registry Platform’ is a case registry system for patients with PV (ClinicalTrials.gov identifier: ChiCTR1900021629). Patients with moderate-to-severe PV who underwent regular treatment with biologics from October 2019 to May 2023 were enrolled in the study. Exclusion criteria: (1) less than 20 weeks of treatment with biologics; (2) less than 4 weeks of CM treatment; (3) use of treatments other than combined emollients; (4) incomplete case registry information; (5) failure to meet remission criteria with treatment. The specific case screening process is illustrated in .
Figure 1. Flow chart of the study.
Chinese medicine use
According to the Traditional Chinese Medicine (TCM) guidelines for psoriasis, herbal prescriptions are provided to patients by TCM physicians based on the syndrome of TCM. Psoriasis is classified into 3 syndromes in TCM: blood-heat syndrome, blood-dryness syndrome and blood-stasis syndrome (Citation18). The basic prescriptions are as follows: (1) Blood-heat syndrome: Liangxue Xiaoyin Formula, consisting of Moutan Cortex 12 g, Paeoniae Radix Rubra 12 g, Imperatae Rhizoma 15 g, Radix Arnebiae 10 g, Smilacis Glabrae Rhizoma 15 g, Saposhnikoviae Radix 10 g, Isatidis Radix 12 g, Glycyrrhizae Radix Et Rhizoma 10 g, etc.; (2) Blood-dryness syndrome: Yangxue Xiaoyin Formula, consisting of Angelicae Sinensis Radix 12 g, Paeonia Radix Alba 15 g, Salvia Miltiorrhizae Radix Et Rhizoma 15 g, Spatholobi Caulis 15 g, Saposhnikoviae Radix 10 g, Smilacis Glabrae Rhizoma 15 g, Lycii Cortex 15 g, Glycyrrhizae Radix Et Rhizoma 10 g, etc.; (3) Blood stasis: Huoxue Xiaoyin formula, consisting of Curcumae Radix 10 g, Ramulus Euonymi 9 g, Sparganii Rhizoma 10 g, Persicae Semen 10 g, Carthami Flos 9 g, Saposhnikoviae Radix 12 g, Lycii Cortex 15 g, Gentianae Macrophyllae Radix 10 g, Clematidis Radix Et Rhizoma 10 g, Spatholobi Caulis 15 g, Glycyrrhizae Radix Et Rhizom 10 g, etc. The herbal formula is taken 200 ml per dose, twice daily.
Patients who received herbal medicines for ≥4 weeks during biologic therapy were classified as the combination group, while those who did not use herbal medicines in the month before biologic therapy, during treatment, and during the follow-up were classified as the biologics group.
Study variables and endpoint
All patients were included in the ‘Psoriasis Registration Platform’ for unified registration and follow-up. The study variables were (1) general information (age, gender, body mass index [BMI]) as well as smoking and alcohol addiction, (2) disease characteristics (PASI score, disease duration, family history, history of previous biologics treatment, and type of TCM syndrome), and (3) treatment regimens (type of biologics and treatment period). The patients were followed up for 24 weeks from cessation of treatment, and relapse was the endpoint event of the study. During follow-up, physicians obtained patients’ PASI scores as a basis for evaluating relapse through offline clinics, Internet healthcare and video telephony.
In this study, lesion remission was defined as a decrease in PASI score of 75% and greater from pretreatment, i.e., achievement of PASI 75. Relapse was defined as an increase in PASI score of 25% of the baseline PASI score after cessation of treatment in patients who had achieved clinical remission, i.e., loss of PASI 75. The time to relapse was defined as the time from cessation of treatment to lesion relapse.
Ethical considerations
The study was designed and conducted in accordance with the principles of the Declaration of Helsinki and clinical research practice guidelines. Ethical approval was obtained from the Institutional Review Board of China–Japan Friendship Hospital (2019-159-K108). Written informed consent was obtained from all patients before the study implementation.
Statistical analysis
Clinical characteristics of the two groups of patients were compared by the χ2 test. Kaplan-Meier curves were employed to demonstrate the cumulative incidence of relapse in the two groups, and log-rank tests were used for comparison between the groups. Furthermore, Cox regression analysis was used to assess the hazard ratios (HRs) for the relapse risk in the combination and biologic groups and to calculate 95% confidence intervals (CIs). To reduce the impact of differences in demographic and clinical characteristics on study outcomes, PSM, a posteriori randomization method, was used to match patients in the biologics and combination groups. The ratio value was 1 while caliper value was 0.2. Statistical analysis was conducted using SPSS 26.0 version 23 (IBM Corp.) and R version 4.3.1, and p < .05 was considered to indicate statistical significance.
Results
Patient characteristics
This study included a total of 509 patients with moderate-to-severe PV treated with biologics, but 118 were excluded due to short treatment period, incomplete follow-up, incomplete case information, etc.; thus, 391 patients were included in the final analysis, including 188 in the combination group and 203 in the biologics group (). Before PSM, differences in baseline characteristics between the two groups were significant. Compared with the biologics group, the combination group had a higher proportion of women (2.6% vs. 32.5%, p = .04) and moderate psoriasis (34.0% vs. 16.7%, p < .001). No statistically significant difference was observed between the two groups in terms of age, BMI, disease duration, family history, smoking and alcohol addiction, type of TCM syndrome, type of biologics, treatment period, history of previous biologics treatments, and PASI 90 response (p ≥ .05). Characteristics of patients in different hospitals can be found in the Supplementary material.
Table 1. Characteristics of patients in the combination and biologics group before and after PSM.
Analysis before PSM
A total of 169 (43.2%) patients experienced relapse during follow-up, including 113 (55.7%) in the biologics group and 56 (28.9%) in the combination group. Kaplan-Meier curve presented the relapse during the follow-up, with the cumulative relapse rate in the combination group being significantly lower than that in the biologics group (p < . 001) (). Multiple Cox regression analysis revealed that adjunctive CM therapy was associated with a reduced risk of psoriasis relapse (HR = 0.680, 95%CI: 0.479–0.965, p = .031). In addition, the type of biologics, disease duration, and PASI 90 response were significantly associated with relapse ().
Figure 2. Cumulative relapse risk curves for the biologics and combination groups before (A) and after (B) PSM.
Figure 3. Forest map by multivariate Cox regression after PSM.
Table 2. Univariate and multivariate cox regression analyses of relapse before PSM.
Analysis after PSM
To reduce the impact of bias, a 1:1 PSM analysis was conducted between the two groups, and matching cohorts of 156 individuals per group were generated. No significant differences were observed in the clinical characteristics of the two groups after PSM, which labeled a good match (). Characteristics of patients included and excluded after PSM can be found in the Supplementary material.
A total of 132 (42.3%) patients in the matched population experienced relapse during follow-up, including 86 (55.1%) in the biologics group and 48 (30.8%) in the combination group. Kaplan–Meier curve analysis revealed that the cumulative risk of relapse in the combination group was significantly lower than that in the biologics group (p < . 001) ().
Multivariate Cox analysis showed that adjunctive CM therapy (HR = 0.42, 95%CI: 0.29–0.60, p < .001) was significantly associated with reduced incidence of relapse. In addition, patients who achieved PASI 90 during treatment had a more optimistic long-term prognosis (HR = 0.30, 95%CI: 0.24–0.55, p < .001), whereas patients with >2 years of disease duration exhibited a higher incidence of relapse (HR = 3.31, 95%CI: 1.45–7.57, p = .004) ().
Subgroup analysis
To assess the benefit from CM in patients with different TCM syndrome and different biologics treatments, subgroup analyses were performed in matched patients ( and Citation5). Adjuvant CM therapy was associated with a reduced risk of relapse after discontinuation of Adalimumab (HR = 0.43, 95% CI = 0.24–0.78, p = .002), Secukinumab (HR = 0.46, 95% CI = 0.28–0.76, p = .003) and Ixekizumab (HR = 0.28, 95% CI = 0.009–0.91, p = .034). Furthermore, both patients with blood-heat syndrome (HR = 0.36, 95% CI = 0.22–0.61, p < .001) and blood stasis syndrome (HR = 0.41, 95% CI = 0.18–0.92, p = .031) benefited from CM. The impact of adjunctive CM therapy on relapse in patients with blood-dryness syndrome was insignificant, however, they showed a tendency of benefiting from CM.
Figure 4. Forest map by multivariate Cox regression in subgroup analysis.
Figure 5. Cumulative relapse risk curves in subgroup analysis. (A) Adalimumab; (B) Secukinumab; (c) Ixekizumab; (d) blood-heat; (e) blood-dryness; (f) blood-stasis.
Discussion
Reducing psoriasis relapse and prolonging the remission period owing to its complex pathogenesis remains a challenge (Citation19,Citation20). Considering the current clinical status of biologics in treating psoriasis, and based on the advantages of CM in treating psoriasis, this study evaluated the effect of adjunctive CM therapy on psoriasis relapse through a prospective cohort study. Our results showed that adjunctive CM therapy was significantly associated with reduced incidence of relapse in patients with moderate-to-severe PV after discontinuation of biologics. This result remained consistent after adjusting for confounders.
Patients with psoriasis frequently experience relapses after discontinuation of biologics (Citation7–9). Previous studies have shown that more than half of patients experience relapse within six months after discontinuing biologics (Citation8), and 95% of patients relapse within 613 days (Citation9). In this study, 55.7% of patients in the biologic group relapsed during the follow-up period, which is similar to the results of previous studies. Furthermore, previous studies have confirmed a trend toward shorter relapse times in psoriasis as the number of treatments with biologics increases (Citation9), which poses a serious test for biologics. The pathogenesis of psoriasis relapse has not been elucidated. ‘Molecular scars’ and TRMs remain in resolved skin after treatment with biologics, which may be the crux of relapse (Citation21,Citation22).
Our study found that adjunctive CM therapy significantly reduced the risk of relapse and that patients treated with either Adalimumab, Secukinumab, or Ixekizumab benefited from CM. Previous studies have reported the advantages of CM in reducing psoriasis relapse (Citation16). In a 12-week pilot trial, the relapse rate in the herbal group (17%) was significantly lower than in the placebo group (67%) (Citation16). In addition, topical application of Chinese herbs has been shown to reduce relapse, and Wang et al. (Citation23) demonstrated that balneotherapy with CM can prolong the remission period in patients with PV in a randomized controlled trial. Guan et al. (Citation24) included 25 studies to evaluate the effectiveness of CM baths combined with ultraviolet irradiation in the treatment of psoriasis, and the results showed that the relapse rate was lower in the combined CM bath group.
The role of adjunctive CM therapy in preventing relapse may be achieved through a multi-component, multi-targeted modulation of inflammatory memory. Previous studies have shown that CM and its active ingredients can downregulate CD8 + TCM in the circulation and CD8 + CD103 + TRM in the skin (Citation17). In addition, CM has been shown to inhibit the reactivation of dermal γδ T cells and down-regulate the expression level of Cyr61 in psoriasis mice, which in turn regulates psoriasis relapse (Citation25–28).
The degree of lesion remission during treatment (achievement of PASI 90) and disease duration were found to influence psoriasis relapse. In this study, patients who achieved PASI 90 during treatment had a lower risk of relapse than those who did not. This result is understandable as relapse is often defined as loss of PASI 75, and patients failure to achieve PASI 90 are more likely to meet the criteria for relapse. Similar results have been obtained in previous studies. Hsien-Yi Chiu et al. (Citation10) found that higher PASI remission rates during treatment were suggestive of longer skin lesion remission after treatment discontinuation. The median time to relapse for patients with psoriasis who achieved PASI 90 during treatment was six months, whereas that for patients who did not was only four months (Citation29). The duration of psoriasis also affects relapse, and this study showed that patients with disease duration ≤2 years had a lower risk of relapse after discontinuing biologics. This may be attributed to the correlation between the number of CD8 + CD103+ TRMs and the progression of the psoriasis course, and early and effective treatment can reduce the accumulation of TRMs in the skin (Citation30). Early intensive treatment with biologics has therefore been promoted by some academics (Citation31).
To the best of our knowledge, this is the first study to provide evidence that adjunctive CM therapy can reduce the risk of psoriasis relapse after discontinuation of biologics. Our study provides a new idea for the prevention and treatment of psoriasis relapse in the current. The combination of rapid alleviation of lesions by biologics and prevention of relapse by adjunctive CM therapy may be able to achieve long-term stable control of psoriasis. However, this study has several limitations. First, this was a nonrandomized observational cohort study, and potential unknown confounders may have remained unadjusted and resulted in bias, despite PSM. Fortunately, our results were robust in subgroup analysis. Second, other factors that may influence psoriasis relapse, such as socioeconomic status, lifestyle, and exercise habits, cannot be estimated in this study. In addition, with only 24 weeks of follow-up in this study, half of the patients had not yet experienced relapse, and therefore information on the median time to relapse is lacking. In the future, longer follow-up could be performed to obtain detailed relapse information, and a randomized controlled trial could be conducted to further confirm our findings.
Conclusions
Adjunctive CM therapy can reduce the risk of psoriasis relapse after discontinuation of biologics, and CM can be considered as an adjunctive option for psoriasis management in the current era of biologics.
Supplemental Material
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We are grateful to all patients and staff who participated in this study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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References
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