INTRODUCTION
Psoriasis, a chronic inflammatory disorder, has been identified as a strong contributor to cardiovascular disease (CVD) with up to 1% absolute increase in CVD risk per year.[1] The inflammatory milieu and the associated cytokines (e.g. interferon-γ, TNF-α, IL-17, 1L-23, IL-6, IL-8, IL-12 and IL-19) involved in the pathogenesis of psoriasis have been causally linked to the cascade of systemic inflammation, cardio-metabolic derangements and CVD.[12] The American College of Cardiology/American Heart Association (ACC/AHA) guidelines have indeed incorporated psoriasis as a CV risk enhancer when calculating the 10-year risk of a CV event.[3]
There is a dearth of evidence regarding CV risk factor treatment thresholds in psoriasis. Statins have shown efficacy in improving lipid profile and CV outcomes in psoriasis,[4] however, currently there is no certain indication for using statins only due to the presence of psoriasis. In a retrospective study, the authors recommended giving statins to patients with intermediate or high CV risk only.[5] Ever-growing evidence on the pleotropic properties of statins, including their anti-inflammatory, immunomodulatory, antioxidant, and improving endothelial function, has instigated the researchers to explore their potential role in causing immunomodulation and affecting disease severity in psoriasis.
However, few studies in this direction have shown inconsistent results and included psoriasis patients irrespective of their CV risk status.[6789101112]
Taking into account the above mentioned considerations, the present study was planned to evaluate the efficacy of rosuvastatin on disease severity, inflammatory, and angiogenic biomarkers when given as add-on to standard treatment in chronic plaque psoriasis patients having CV risk based on the current ACC/AHA guidelines with an aim to dig deeper into understanding the most appropriate candidates for statin therapy among psoriasis patients and exploring the potential role in psoriasis beyond the CV benefit offered by this class of lipid lowering therapy.
METHODOLOGY
Study design
The rosuvastatin on disease severity, inflammatory and angiogenic biomarkers in chronic plaque psoriasis patients (RoSInA-P3) was an academic, investigator-initiated, single-center, nonrandomized, assessor blind, parallel-group, controlled clinical trial conducted collaboratively by the departments of pharmacology, dermatology and venereology, and internal medicine at a tertiary care hospital in Haryana. The study was conducted between February 2023 and March 2024 (CTRI/2023/02/049424).
Study participants
Patients visiting the dermatology and venereology outpatient department (OPD) were screened for eligibility. Inclusion criteria were age 18–65 years of either gender, mild-to-moderate chronic plaque psoriasis (psoriasis area and severity index [PASI] score up to 10), and willingness to give informed consent. Exclusion criteria were severe forms of psoriasis, guttate psoriasis, psoriatic arthritis, patients on systemic treatment for psoriasis, known allergy or contraindication to statins, active liver disease, myopathy, and pregnant or lactating women.
Study interventions
Eligible subjects were referred to the Medicine OPD, where they were evaluated for CV risk and statin therapy eligibility based on ACC/AHA guidelines.[3] Patients having intermediate and high-risk were eligible for statin therapy (Group A), whereas those with low or borderline risk were not (Group B). After a 2-week washout period, both the groups received study interventions for 12 weeks as: (1) Group A: rosuvastatin (10 and 40 mg daily for intermediate and high-risk categories, respectively) along with the standard topical treatment; and (2) Group B: standard topical treatment. Standard treatment was given by dermatologist according to the American Academy of Dermatology guidelines[13] and encompassed topical corticosteroids (clobetasol propionate 0.05% w/w) and keratolytic (salicylic acid 3% or 6% w/w) agents and remained constant over the 12 week study period.
Efficacy and safety assessment
The primary endpoint was the mean change in PASI score at 12 weeks from baseline. Secondary endpoints included proportion of patients achieving at least 50% and 75% reduction in PASI score from baseline (PASI50 and PASI75) at 12 weeks; mean change in dermatology life quality index (DLQI) scores, lipid profile, serum high-sensitivity C-reactive protein (hs-CRP), vascular endothelial growth factor (VEGF), and IL-17 levels at 12 weeks from baseline. Blinded endpoint assessment was done for PASI and DLQI by an independent dermatologist unaware of the assigned treatment.
Serum hs-CRP, VEGF, and IL-17 levels were estimated by quantitative sandwich enzyme-linked immunosorbent assay technique.
Safety assessment was done by active query and patient-reported adverse events (AEs) during each follow-up visit (4, 8, and 12 weeks); and liver function tests (LFTs) at 12 weeks.
Sample size calculation
Sample size was calculated based on data from the study by Trong et al[8] showing mean reduction in PASI score of 8.63 in simvastatin group versus 5.34 in the control group with standard deviation of 3 in both groups, with the assumption that rosuvastatin would have at least similar efficacy. Considering a desired power of 80% and alpha error of 5%, sample size was calculated as 14 patients in each group. To account for around 20% dropouts, a minimum of 18 patients were needed in each group.
Statistical analysis
Data were subjected to Shapiro–Wilk normality test and expressed as mean ± SD or median (interquartile range), depending upon the distribution for continuous variables and numbers (percentages) for categorical variables. Primary analyses for all outcomes were done by modified intention to treat (mITT) principle and patients with at least one follow-up site visit after enrolment were included in the study. Missing data were handled with last observed carried forward principle.
For primary outcome, sensitivity analysis was carried out by best and worst case scenario. Proportions were compared using Chi-square tests with continuity correction or Fisher’s exact test. For PASI scores, between and within groups comparisons were analyzed using generalized linear models-repeat measures and repeated measures analysis of variance, respectively.
Mean changes in various parameters were compared between groups using analysis of covariance with baseline value as covariate. Correlation of change in PASI score with biochemical parameters were analyzed using Pearson’s correlation coefficient. Two-sided P < 0.05 was considered statistically significant.
Analyses were performed using IBM SPSS (Statistical Package for the Social Sciences; SPSS Inc., Chicago, USA) software (trial version v 29.0).
Ethical considerations
Approval was obtained from the Institute Biomedical Research Ethics Committee (BREC/22/TH/Pharma-01and BREC/23/TH-Pharma/06). The study was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki. All subjects gave written informed consent; and data confidentiality was maintained.
RESULTS
Out of the total 94 patients screened, 48 met the inclusion criteria, and 24 were eligible for statin therapy. Seven and 5 patients in rosuvastatin and standard therapy groups, respectively, were lost to follow-up; hence, 17 and 19 patients were available for mITT analysis in the two groups, respectively [Figure 1]. In rosuvastatin group, the mean age of patients was greater and there were more patients with current or past history of smoking.
Both the groups were comparable for disease characteristics and biochemical parameters [Table 1].
At 12 weeks, the mean (SD) change from baseline PASI was −2.34 (2.81) in the rosuvastatin and −1.93 (3.33) in standard therapy groups (P = 0.38) [Table 2]. Change in PASI score with time within the two groups is depicted in Table 3; a statistically significant reduction in PASI score from baseline was observed in both groups (P = 0.002 and 0.026 in rosuvastatin and standard groups, respectively). On post hoc analysis, significant reduction in PASI was observed as early as 4 weeks compared to baseline in rosuvastatin group only and the reduction was consistently significant at 8 and 12 weeks also.
Between group comparison for time group interaction, however, did not yield statistically significant difference. The results of sensitivity analysis for primary outcome were similar to the primary analysis.
In rosuvastatin group, PASI50 at 4, 8 and 12 weeks were 3 (17.64%), 2 (11.76%), and 5 (29.41%), respectively, whereas in standard therapy group, they were 0, 2 (10.52%) and 5 (26.31%) (P = 0.05, 0.9 and 0.83 at 4, 8 and 12 weeks, respectively) [Figure 2a]. PASI75 was observed in 1 (5.88%) and 3 (17.64%) patients at 8 and 12 weeks, respectively in rosuvastatin group compared to only 2 (10.52%) patients in standard group at 12 weeks (P = 0.29 at 8 weeks and 0.53 at 12 weeks) [Figure 2b].
Baseline-adjusted mean change in DLQI and biochemical parameters at 12 weeks from baseline were not significant in the two groups [Table 2]. A statistically significant linear correlation of change in PASI scores was observed with change in triglycerides (r = 0.35, P = 0.03) and very low-density lipoprotein cholesterol levels (r = 0.36, P = 0.03) but not with change in other lipid, inflammatory and angiogenic markers.
The number of AEs reported was 12 and 7 in the rosuvastatin and standard groups, respectively, and included nausea, vomiting, weakness, dizziness, and rashes; all were mild and resolved spontaneously. No significant derangement in LFT parameters was observed.
DISCUSSION
Our study is an unprecedented attempt to demonstrate any additional potential benefit of rosuvastatin on psoriasis severity when used in the CV risk category-based recommended dose used in clinical practice. Our results are in agreement with previous studies reporting the beneficial effect of statins (atorvastatin and simvastatin) in reducing PASI scores[67891011] when given as adjunctive therapy in psoriasis. Considering the salient pharmacological characteristics of rosuvastatin, such as low penetration into extrahepatic tissues, lesser potential for CYP3A4 drug interactions, more pronounced LDL cholesterol-lowering capacity than other statins, and long half-life,[14] it was selected as the study drug.
Sarian and Bolotna also demonstrated significant reduction in PASI score with rosuvastatin in psoriasis.[12] In a meta-analysis, statins were reported to confer greater improvement in PASI score compared to standard therapy.[15] It is, however, worth mentioning that in contrast to our study, all previous studies[6789101112] were conducted in psoriasis patients irrespective of their CV risk and indication for statin therapy.
Both arms had a reduction in DLQI scores, although baseline-adjusted mean change was not significantly different, similar to a previous study on atorvastatin.[11] As in earlier studies, patients exhibited high levels of inflammatory (hs-CRP and IL-17) and proangiogenic (VEGF) markers at baseline.[1112] There was a decline in hs-CRP levels with rosuvastatin as reported earlier.[12] Atorvastatin, however, failed to demonstrate a reduction in hs-CRP levels after 6 months in another study.[11] Statins exhibit anti-inflammatory effects by down-regulating adhesion molecules on leukocytes and endothelial cells, and inhibiting helper T cells activation.[12] A possible explanation for the higher anti-inflammatory effect of rosuvastatin may be the drug’s ability to enter the systemic circulation in very high concentrations as compared to other statins.
IL-17 contributes to various pathological processes in psoriasis, mainly keratinocyte proliferation and stimulation to produce proinflammatory cytokines and chemokines.[16] We observed a declining trend in the levels of IL-17 in rosuvastatin (mean ± SD [pg/mL]: 8.77 ± 6.95 and 7.73 ± 5.95 at 0 and 12 weeks, respectively, P = 0.28) but not in standard group (7.65 ± 6.46 and 8.29 ± 7.05 at 0 and 12 weeks, respectively, P = 0.67) which however did not reach statistical significance similar to the study by Garshick et al.,[17] a possible reason for which may be short duration of study. Both the arms experienced decline in VEGF levels from baseline in contrast to an earlier study.[12]
Absence of any significant correlation among clinical (PASI) and biochemical parameters implies the improvement in disease severity to be independent of lipid-lowering, anti-inflammatory, and antiangiogenic properties of rosuvastatin. However, whether this was due to study or disease-related intrinsic factors demands further investigations. It is worth emphasizing that complex immune-pathogenic mechanisms with a myriad of cytokines (e.g., interferon-γ, TNF-α, IL-17, 1 L-23, IL-6, IL-8, IL-12 and IL-19) are involved in psoriasis and the most appropriate inflammatory marker for research is yet to be identified.
The study has a few limitations. Due to an existing dilemma regarding the absolute need for statin therapy in psoriasis, allocation to treatment was done in a nonrandomized manner according to the patients’ CV risk-based statin eligibility. Patients with mild-to-moderate psoriasis were included; hence, the potential benefit of rosuvastatin may not be evident in severe plaque psoriasis.
This was an open labelled study however assessor blinding was done to prevent ascertainment bias. Statin-induced myopathy was not monitored by the levels of creatine kinase-myocardial band, although patients were periodically assessed clinically and instructed to report in case of occurrence of any related symptoms. The study was single-centric limiting the generalizability of findings.
Finally, the results must be viewed in the light of chronic plaque psoriasis only.
CONCLUSION
Rosuvastatin given as add-on to standard psoriasis treatment caused a faster improvement in disease severity and improvement in quality of life; the drug also exhibited anti-inflammatory and antiangiogenic properties, potentially interfering with the disease pathogenic mechanisms. Hence, we propose considering statin (rosuvastatin) as an add-on treatment option for chronic plaque psoriasis patients having intermediate or high CV risk based on ACC/AHA guidelines, and not all psoriasis patients.
Conflicts of interest
There are no conflicts of interest.