Abstract
Background
Hyperlipidemia is prevalent in primary immune thrombocytopenia (ITP) and may exacerbate bleeding severity and compromise treatment responses. Statins possess lipid-lowering and anti-inflammatory properties, but their influence on corticosteroid therapy in ITP patients with hyperlipidemia remains unclear.
Objectives
This study aimed to compare the efficacy and safety of initial corticosteroid therapy between patients with or without concomitant statin use for pre-existing hyperlipidemia in a cohort of newly diagnosed ITP patients.
Design
A multicenter retrospective propensity score-matched study.
Methods
Newly diagnosed ITP patients with pre-existing hyperlipidemia from 9 medical centers were analyzed. Patients were divided into 2 groups based on statin use (statin vs. non-statin). Propensity score matching (PSM) was employed to balance baseline characteristics. Treatment outcomes, including response rates, duration of response (DOR), and safety, were compared.
Results
After PSM, 104 patients (52 per group) were included. Baseline characteristics were comparable. Initial response rates were similar between the statin and non-statin groups (67.3% vs. 65.4%, P = 0.836), with the 95% confidence interval (CI) for the between-group risk difference ranging from -15.83% to 19.51%. The median time to response was numerically shorter in the statin group, although this difference did not reach statistical significance (4 [2-8] days vs. 5 [2-12] days, P = 0.054). Notably, the sustained response (SR) rate at 6 months was significantly higher in the statin group compared to the non-statin group (50.0% vs. 30.8%, P = 0.046), with the 95% CI for the between-group risk difference ranging from 0.41% to 36.25%. Kaplan-Meier analysis also demonstrated a significant longer duration of response (DOR) in the statin group (P = 0.044). No serious adverse events were observed in either group during follow-up.
Conclusion
In this retrospective, propensity score-matched cohort, concomitant statin use was associated with higher 6-month SR rates and longer DOR in newly diagnosed ITP patients with pre-existing hyperlipidemia, without an apparent increase in serious adverse events. These observational findings warrant further validation in larger, prospective cohorts.
Keywords: corticosteroids, hyperlipidemia, primary immune thrombocytopenia, statins
Plain language summary
Some patients with immune thrombocytopenia (ITP) also have hyperlipidemia, which may exacerbate bleeding severity and compromise treatment responses. Statins, commonly used for lipid management, possess additional anti-inflammatory properties. However, the efficacy and safety of combining statins with corticosteroid therapy in ITP patients with pre-existing hyperlipidemia remain unclear. This study was designed to investigate this clinical question. We conducted a retrospective analysis of medical records from nine hospitals involving newly diagnosed ITP patients with comorbid hyperlipidemia. Patients were categorized into two groups: one receiving corticosteroid combined with statins, and the other receiving corticosteroid alone. To ensure comparability, propensity score matching (PSM) was employed to balance baseline characteristics between the two groups. Ultimately, treatment outcomes and safety profiles were compared between 52 patients in the statin group and 52 patients in the non-statin group after matching. The initial response rates were comparable between the two groups (67.3% in the statin group vs. 65.4% in the non-statin group), with no significant difference in the time to response. The key difference emerged in long-term outcomes. At the 6-month follow-up, the proportion of patients maintaining a satisfactory therapeutic response was significantly higher in the statin group (50.0%) compared to the non-statin group (30.8%). Furthermore, the duration of treatment response was significantly longer among patients receiving statins. Importantly, no serious adverse events were reported in either group during the study period. For ITP patients with concomitant hyperlipidemia, the addition of statins to standard corticosteroid therapy may enhance long-term treatment efficacy. This combination enables a greater proportion of patients to maintain a stable platelet count over the long term without increasing the risk of serious adverse events.
Introduction
Primary immune thrombocytopenia (ITP) is among the most prevalent autoimmune hemorrhagic diseases, with an annual incidence of approximately 2-10 per 100,000 adults. 1 The pathogenesis of ITP involves a complex interplay of immune dysregulation, including anti-platelet autoantibody production, impaired megakaryocyte maturation, and imbalance in immune cell subsets.2,3 Emerging data suggest that altered expression of lymphocyte activation and adhesion molecules correlates with disease activity and therapeutic response in ITP, underscoring ongoing immune activation beyond platelet clearance alone. 4 Although platelet count remains the primary determinant of bleeding risk in ITP, accumulating evidence indicates that platelet dysfunction also contributes to bleeding severity. 5 Initial therapies for adults with ITP primarily include corticosteroids and intravenous immunoglobulin (IVIg), while anti-D immunoglobulin may be considered in selected Rh(D)-positive, non-splenectomized patients. 6 The reported initial response rates of corticosteroids ranging from 60% to 80%. 7 However, relapse is common, and long-term sustained response (SR) rate is only approximately 20-30%. 1 In relapsed or refractory cases, a range of subsequent treatments are available. These include medical therapies such as thrombopoietin receptor agonists (TPO-RAs), rituximab, and fostamatinib. 8 Splenectomy, a surgical option with high rates of durable remission, may also be considered, though it is typically reserved for patients who have failed multiple medical treatments due to its associated risks. 9 A major concern with corticosteroids is their impact on glucolipid metabolism, usually resulting in hyperglycemia and hyperlipidemia.
Hyperlipidemia is commonly observed in ITP and other autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).10,11 Emerging evidence highlights the role of lipid metabolism in modulating immune cell function and disease progression of autoimmune disorders. 12 Consistently, our recent study revealed a high prevalence of metabolic syndrome, including hyperlipidemia, in ITP patients. In this study, 50.7% of patients with ITP had hyperlipidemia, and 39.7% had pre-existing metabolic diseases prior to ITP treatment. Compared with patients with normal lipid levels, patients with ITP and hyperlipidemia have lower platelet counts and more severe bleeding symptoms. 13 These data underscore the clinical complexity of managing ITP patients with coexisting hyperlipidemia.
Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, remain the cornerstone of lipid-lowering therapy due to their efficacy in reducing low-density lipoprotein (LDL) levels and decreasing the risk of cardiovascular events. 14 Beyond the lipid-lowering effects, statins also exhibit immunomodulatory properties, such as modulating T-cell activity and inhibiting inflammatory cytokine production, which could be beneficial in autoimmune conditions. 15 Prior mechanistic studies have also demonstrated that atorvastatin can modulate platelet activation and inhibitory signaling pathways, and improve bone marrow endothelial progenitor cell function, thereby restoring the hematopoietic microenvironment, particularly in patients with steroid-resistant ITP.16–18 These findings suggest that statins may confer therapeutic benefits in ITP through mechanisms beyond cholesterol reduction, providing a biological rationale for their adjunctive use alongside corticosteroids. Therefore, while statins are standard therapy for hyperlipidemia, their adjunctive role in ITP remains unevaluated in large cohorts. This study aims to address this gap by evaluating the efficacy and safety of corticosteroids plus statins in newly diagnosed ITP patients with pre-existing hyperlipidemia, using a multicenter retrospective analysis using PSM.
Methods
Study design, population, and data collection
The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, and the corresponding checklist was followed throughout the manuscript preparation. 19
This study was conducted in accordance with the Declaration of Helsinki. This retrospective multicenter study was approved by the Institutional Review Board (IRB) of Qilu Hospital of Shandong University (approval number KYLL-2020(KS)-362, date January 1, 2021). The participating centers acknowledged the IRB approval from the coordinating center according to their institutional requirements and contributed anonymized clinical information. Because the study involved only retrospective review of anonymized clinical data, the requirement for informed consent was waived by all the centers included.
This multicenter retrospective study included newly diagnosed ITP patients with a history of hyperlipidemia from 9 medical centers between January 2020 and June 2024. The sample size was determined by the number of eligible patients available during this period. The participating centers were Qilu Hospital of Shandong University, Jining No. 1 People’s Hospital, Central Hospital Affiliated to Shandong First Medical University, Heze Municipal Hospital, Qilu Hospital of Shandong University Dezhou Hospital, Jinan City People’s Hospital, Tai’an Central Hospital, Binzhou Medical University Hospital, and North China University of Science and Technology Affiliated Hospital. Data collection was standardized across centers using a uniform electronic case report form designed by Qilu Hospital of Shandong University. All investigators were trained to ensure consistent data entry and adherence to predefined variable definitions. Clinical data collected included demographic characteristics, initial treatment regimens, lipid-lowering therapy details, concomitant treatments, adverse effects, platelet counts, and bleeding manifestations. Bleeding severity was assessed using the Chinese bleeding rating system, which is composed of age scale and bleeding manifestation scale. 20 We only calculated the score of bleeding manifestations. Three experts independently reviewed the medical records of each patient. Discrepancies were resolved through discussion until consensus was reached. Missing data were assessed across centers; variables with missingness > 5% were excluded from the primary analysis, while sporadic missing values (<5%) were handled using multiple imputation.
Hyperlipidemia was defined according to the 2023 China Guidelines for Lipid Management as any of the following fasting lipid abnormalities: total cholesterol (TC) ≥ 6.2 mmol/L, triglycerides (TG) ≥ 2.3 mmol/L, LDL-C ≥ 4.1 mmol/L, or high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol/L. 21 Statin therapy has been initiated prior to or at the time of ITP diagnosis in the statin group. Treatment adherence was confirmed through reviewing of medical records and telephone follow-up, and all included patients in the statin group maintained continuous statin therapy throughout the follow-up period without interruption. We recorded patients’ lipid profiles prior to initiation of corticosteroid therapy and monitored during follow-up. Adverse events (AEs), particularly those potentially related to statin therapy, were recorded through telephone follow-up and verified by retrospective review of medical records. The occurrence, type, and timing of each AE were documented in detail from the initiation of treatment to the last follow-up. Based on previous literature and clinical relevance,22,23 we summarized adverse events associated with statin and corticosteroid therapy, including liver dysfunction (elevation of ALT or AST more than three times the upper limit of normal), stomach upset (gastrointestinal discomfort related to therapy), weight gain (≥5% increase from baseline body weight), new-onset hypertension (new diagnosis or initiation of antihypertensive therapy), and new-onset hyperglycemia (fasting glucose ≥ 7.0 mmol/L or new use of antidiabetic medication).
Eligibility criteria
All included patients met the diagnostic criteria for newly diagnosed ITP established by the Chinese Medical Association. 20 Inclusion criteria were aged ≥ 18 years, newly diagnosed, a history of hyperlipidemia, and receipt of corticosteroid-based initial therapy. Corticosteroid regimen included dexamethasone (40 mg/day for 4 days, up to 2 cycles), methylprednisolone (1-2 mg/kg/day) or prednisone (1 mg/kg/day with tapering over 6 weeks). Patients who received concomitant ITP-specific therapies (e.g. TPO-RAs or rituximab) at initial diagnosis were excluded. Short-term IVIg or platelet transfusion was permitted in cases of severe bleeding. Those experiencing treatment failure or relapse received ITP-specific salvage therapies, including IVIg, TPO-RAs, rituximab, vincristine, cyclosporine, decitabine, or danazol.
Response criteria
Treatment response was evaluated according to the Chinese ITP guidelines. 24 At day 14, we assessed the initial treatment response. Complete response (CR) was defined as platelet counts ≥ 100 × 109/L with absence of bleeding. Response (R) as platelet counts ≥ 30 × 109/L with at least a twofold increase from baseline and absence of bleeding. And no response (NR) as platelet counts < 30 × 109/L, or < 2-fold increase from baseline, or the presence of bleeding. Time to response (TTR) was calculated from treatment initiation to CR or R. Duration of response (DOR) was defined from the first achievement of CR or R to relapse. Relapse was defined as a drop in platelet count to < 30 × 109/L, or < 2-fold increase of the baseline platelet count, or bleeding after the achievement of CR or R. Sustained response (SR) was defined as continued response for ≥ 6 months without additional ITP-specific therapies after initial response.
Propensity score matching
To minimize confounding factors and selection bias, we employed PSM to balance baseline characteristics between the statin and non-statin groups. Patients were matched 1:1 using nearest-neighbor matching without replacement and a caliper of 0.05 was used. Baseline variables included in the PSM model were age, sex, bleeding score, BMI, absolute neutrophil count/absolute lymphocyte count (ANC/ALC ratio), smoking, initial platelet count, duration of hyperlipidemia history, corticosteroid type, ITP-additional therapy, and concurrent treatments. Balance was assessed using standardized mean difference (SMD), with an absolute SMD < 0.10 considered balanced. Covariates with SMD greater than 0.1 were considered imbalanced and were further included in the conditional logistic regression model for additional analysis. Patients outside the region of common support or without an eligible match were excluded from the matched analyses. Following PSM, 52 matched patients remained in each group.
Statistical analysis
Continuous data were presented as mean ± standard deviation (SD) or median (range) and compared using Student’s t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the chi-square test or Fisher’s exact test. To identify the predictors of response, multivariate logistic regression analysis was performed, with results reported as odds ratios (OR) and 95% confidence intervals (CI). Kaplan-Meier survival analysis was used to evaluate the duration of response (DOR) between the 2 groups. A P-value < 0.05 was considered statistically significant. Statistical analyses were conducted using SPSS version 27.0 and R software. Relative risk (RR) was calculated to compare the frequency of AEs between statin and non-statin groups.
Results
Patients’ characteristics
We retrospectively reviewed the medical records of 496 ITP patients with concurrent hyperlipidemia. According to the inclusion and exclusion criteria, and during follow-up, 309 patients were excluded. Among the 137 patients who did not meet the inclusion criteria, 56 had secondary thrombocytopenia, 37 were not newly diagnosed ITP, 29 had received other ITP-specific therapies during initial treatment, and 15 had insufficient clinical records. A total of 172 patients were excluded due to missing essential baseline data or lost to follow-up, including 35 with missing baseline lipid profiles or bleeding assessments, 26 with missing key outcome data at day 14, 96 lost to follow-up before 6 months, and 15 with incomplete statin exposure information. Ultimately, 187 patients were included in the final analysis, with 65 patients in the statin group and 122 patients in the non-statin group (Figure 1). Baseline characteristics were compared between the 187 included patients and the 274 excluded patients with available baseline data (excluding 37 patients with missing baseline data). No significant differences were observed in age, sex, baseline platelet count, ANC/ALC ratio, BMI, or smoking history between the two groups. Notably, bleeding scores were significantly higher in the excluded cohort than in the included cohort [2 (0–6) vs. 1 (0–8), P = 0.037], which may be due to the presence of relapsed refractory ITP among excluded patients, who are more likely to exhibit more severe bleeding symptoms (Supplementary Table 1).
Figure 1.
Flow diagram of study design A total of 496 ITP patients with pre-existing hyperlipidemia were assessed for eligibility. Of these, 309 patients were excluded based medical record screening or during follow-up: 137 patients did not meet inclusion criteria, and 172 patients were missing essential baseline data or lost to follow-up. The remaining 187 patients were included in the analysis, with 65 patients in the statin group and 122 patients in the non-statin group. Propensity score matching yielded 52 patients in each of the 2 groups with comparable baseline characteristics.
The median age in the statin group was significantly higher compared to the non-statin group (65 [34-87] vs. 53 [20-86] years, P < 0.001). No significant differences were observed between the 2 groups in other baseline characteristics, including gender, initial platelet count, BMI, ANC/ALC ratio, bleeding score, smoking history, duration of hyperlipidemia history, types of corticosteroid use, ITP-additional treatments (IVIg or platelet transfusion), and other concurrent therapies. After PSM, 52 patients remained in each group, with all matched covariates showing balanced distributions (all P > 0.05; Table 1). The median (range) age was 65 (34-82) years in the statin group and 65 (30-86) years in the non-statin group. The median (range) platelet count on diagnosis was 10 (1-29) × 109/L in the statin group and 11 (1-25) × 109/L in the non-statin group. Mucous bleeding was the most common bleeding symptoms with no obvious difference in bleeding scores between the 2 groups. The ANC/ALC ratio and BMI values were also balanced. The median duration (range) of hyperlipidemia history was 4.5 (0.8-9.5) and 4.5 (1–10) years for the statin group and non-statin group, respectively. The median duration of statin treatment was 2 years. Dexamethasone was the most frequently applied corticosteroid type in both groups (44.2% in the statin group vs. 53.8% in the non-statin group). Use of metformin and ITP-additional treatments was also similar between the groups. We also analyzed variables related to statin use that were not included in the PSM model. Before matching, patients in the statin group had a significantly higher prevalence of coronary heart disease (47.7% vs. 9.8%, P < 0.001) and old cerebral infarction (21.5% vs. 4.1%, P < 0.001), whereas the proportion of hypertension did not differ significantly between groups. After matching, the prevalence of coronary heart disease remained significantly higher in the statin group (46.2% vs. 11.5%, P < 0.001), while differences in old cerebral infarction and hypertension were no longer significant. Regarding lipid parameters, LDL-C, and total cholesterol levels were significantly lower in the statin group before matching, and this difference persisted after matching (LDL-C: 2.54 vs. 3.06 mmol/L, P = 0.007; TC: 4.45 vs. 5.18 mmol/L, P = 0.003; Supplementary Table 2).
Table 1.
Patient demographic and characteristics.
| | Pre-PSM (n = 187) | P | SMD | Post-PSM (n = 104) | P | SMD | ||
|---|---|---|---|---|---|---|---|---|
| Statin (n = 65) | Non-statin (n = 122) | Statin (n = 52) | Non-statin (n = 52) | |||||
| Median age (range), years | 65 (34-87) | 53 (20-86) | <0.001 | 0.047 | 65 (34-82) | 65 (30-86) | 0.912 | 0.055 |
| Female, n (%) | 46 (70.8) | 76 (62.3) | 0.247 | 0.18 | 36 (69.2) | 33 (63.5) | 0.534 | 0.122 |
| Median initial platelet count (range), × 109/L | 10 (1-29) | 7 (1-25) | 0.199 | 0.199 | 10 (1-29) | 11 (1-25) | 0.757 | 0.047 |
| Median BMI (range), kg/m2 | 24.4 (17.3-36.4) | 24.5 (17.2-35) | 0.993 | 0.04 | 24.5 (17.3-36.4) | 24.7 (17.2-32.4) | 0.361 | 0.083 |
| Median ANC/ALC ratio (range) | 2.3 (0.76-16.55) | 2.6 (0.64 -9.2) | 0.897 | 0.198 | 2.08 (0.76-16.55) | 3.08 (0.64-8.14) | 0.161 | 0.056 |
| Smoking, n (%) | 14 (21.5) | 24 (19.7) | 0.763 | 0.046 | 11 (21.2) | 12 (23.1) | 0.813 | 0.046 |
| Median bleeding score (range) | 2 (0-6) | 1 (0-8) | 0.127 | 0.187 | 1.5 (0-6) | 1 (0-5) | 0.26 | 0.05 |
| Median duration (range) of hyperlipidemia history, years | 4.5 (0.8-13) | 4 (1-10) | 0.811 | 0.033 | 4.5 (0.8-9.5) | 4.5 (1-10) | 0.837 | 0.031 |
| Corticosteroid type, n (%) | ||||||||
| - Dexamethasone | 33 (50.8) | 61 (50) | 0.92 | 0.02 | 23 (44.2) | 28 (53.8) | 0.327 | 0.19 |
| - Methylprednisolone | 11 (16.9) | 27 (22.1) | 0.399 | 0.012 | 9 (17.3) | 8 (15.4) | 0.791 | 0.052 |
| - Prednisone | 21 (32.3) | 34 (27.9) | 0.526 | 0.097 | 20 (38.5) | 16 (30.8) | 0.41 | 0.162 |
| ITP-additional therapy, n (%) | ||||||||
| - IVIg | 8 (12.3) | 13 (10.7) | 0.748 | 0.058 | 6 (11.5) | 4 (7.7) | 0.506 | 0.12 |
| - Platelet transfusion | 26 (40) | 37 (30.3) | 0.195 | 0.204 | 18 (34.6) | 17 (32.7) | 0.836 | 0.041 |
| Other concurrent treatments, n (%) | ||||||||
| - Metformin | 10 (15.4) | 13 (10.7) | 0.348 | 0.13 | 8 (15.4) | 6 (11.5) | 0.566 | 0.113 |
Abbreviation: PSM, propensity score-matching; SMD, standardized mean difference; ANC/ALC, absolute neutrophil count/absolute lymphocyte count; IVIg, intravenous immunoglobulin.
There were 3 types of lipid-lowering regimens in the statin group—atorvastatin (20 mg nightly), rosuvastatin (10 mg nightly), and simvastatin (20 mg nightly). Throughout the follow-up period, patients in the statin group continued statin therapy for lipid lowering, and no patients discontinued statin treatment. Patients in the statin group had significantly lower concentrations of LDL-C and TC compared to those in the non-statin group, validating the lipid-lowering efficacy of statins in our cohort (Table 2). Among the 3 kinds of statins, rosuvastatin showed more pronounced LDL-lowering efficacy (Table 3, P = 0.008).
Table 2.
Blood lipid data of the statin group and the non-statin group after PSM.
| | Statin (n = 52) | Non-statin (n = 52) | P |
|---|---|---|---|
| LDL-C (mmol/L) | 2.54 ± 0.95 | 3.06 ± 0.96 | 0.007 |
| HDL-C (mmol/L) | 1.26 ± 0.36 | 1.14 ± 0.37 | 0.097 |
| TG (mmol/L) | 2.06 ± 1.36 | 1.92 ± 1.02 | 0.533 |
| TC (mmol/L) | 4.45 ± 1.32 | 5.18 ± 1.18 | 0.003 |
Abbreviation: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol.
Tables 3.
Lipid-lowering effects of different statins.
| | Atorvastatin (n = 33) | Rosuvastatin (n = 15) | Simvastatin (n = 4) | P |
|---|---|---|---|---|
| LDL-C (mmol/L) | 2.79 ± 1.03 | 1.94 ± 0.68 | 1.89 ± 0.3 | 0.008 |
| HDL-C (mmol/L) | 1.31 ± 0.38 | 1.11 ± 0.3 | 1.4 ± 0.33 | 0.149 |
| TG (mmol/L) | 2.11 ± 1.41 | 2.13 ± 1.41 | 1.43 ± 0.49 | 0.634 |
| TC (mmol/L) | 4.69 ± 1.37 | 3.97 ± 0.92 | 4.29 ± 1.97 | 0.204 |
Abbreviation: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol.
Treatment efficacy
There was no significant difference in the overall initial response rate between the statin group and the non-statin group at day 14 [67.3% (35/52) vs. 65.4% (34/52), P = 0.836], with the 95% CI for the between-group risk difference ranging from -15.83% to 19.51%. Additionally, no significant difference was observed in the initial complete response (CR) rate between the two groups (34.6% vs. 30.8%, P = 0.676). The median platelet count at day 14 was 86 (5 - 228) in the statin group compared to 80.5 (1 - 232) in the non-statin group (P = 0.361). The median time to response (TTR) tended to be shorter in the statin group compared to the non-statin group (4 [2-8] days vs. 5 [2-12] days), although the difference was not statistically significant (P = 0.054; Table 4).
Table 4.
Treatment efficacy of ITP patients with hyperlipidemia.
| | Statin (n = 52) | Non-statin (n = 52) | P |
|---|---|---|---|
| Initial response at day 14, n (%) | 35 (67.3) | 34 (65.4) | 0.836 |
| Initial CR at day 14, n (%) | 18 (34.6) | 16 (30.8) | 0.676 |
| Median platelet count at day 14 (range), × 109/L | 86 (5-228) | 80.5 (1-232) | 0.361 |
| Median TTR (range), day | 4 (2-8) | 5 (2-12) | 0.054 |
| SR at 6 months, n (%) | 26 (50) | 16 (30.8) | 0.046 |
Abbreviation: CR, complete response; TTR, time to response; SR, sustained response.
Notably, the 6-month SR rate was markedly higher in the statin group compared to the non-statin group [50.0% (26/52) vs. 30.8% (16/52), P = 0.046], with the 95% CI for the between-group risk difference ranging from 0.41% to 36.25%. During the follow-up period, 9 patients in the statin group experienced relapse, including 3 developed to refractory ITP; while 18 patients in the non-statin group relapsed, including 7 developed to refractory disease. Kaplan-Meier analysis demonstrated a significant longer duration of response (DOR) in the statin group throughout the follow-up period (P = 0.044; Figure 2), indicating that statins contribute to favorable long-term therapeutic effects of corticosteroids in newly diagnosed ITP patients with pre-existing hyperlipidemia.
Figure 2.
Kaplan–Meier curves for duration of response (DOR) Kaplan–Meier curves demonstrated that the DOR was significantly longer in the statin group compared to the non-statin group (P = 0.044).
Relation between baseline characteristics and treatment response
We performed a multivariate logistic regression analysis in the pre-matched cohort to identify the influencing factors on SR rate at 6 months. It was shown that statin use was the only independent factor associated with improved SR rate. Compared with corticosteroid monotherapy, combination therapy of statins plus corticosteroids was a favorable factor for SR, yielding an OR of 2.19 (P = 0.027; 95% CI: 1.09-4.37). Other factors—including age, sex, BMI, smoking, ANC/ALC ratio, initial platelet count, and bleeding score—were not significant associated with SR (all P > 0.05; Figure 3).
Figure 3.
Multivariate logistic regression analysis of prognosis factors on SR rate. Multivariate logistic regression analysis demonstrated that statin use was the only independent factor significantly associated with improved SR rate.
We calculated the SMD for all included variables before and after PSM (Table 1). We found that some variables, such as sex, corticosteroid type, metformin use, and IVIg use, still had SMD values greater than 0.1 after matching. To further eliminate potential confounding effects, we conducted a conditional logistic regression analysis including these variables together with statin use. The results showed that statin use remained the only independent factor significantly associated with an increased SR rate (OR = 2.058, 95% CI: 1.021-4.146, P = 0.043). Other variables, such as sex, IVIg use, metformin use, and corticosteroid type, showed no significant associations (Supplementary Table 3). This confirms that the residual imbalance did not confound the primary association.
Safety
No deaths were reported during the entire treatment and follow-up period. A summary of adverse events is presented in Table 5. Overall, the combination therapy of corticosteroids and statins was well tolerated. Among patients receiving statin therapy, 3 cases of mild liver dysfunction were observed during the follow-up, compared to 1 case in the non-statin group, and all of these occurred within the first month of follow-up. Other adverse events—including new-onset hypertension, new-onset hyperglycemia, stomach upset, and weight gain—were consistent with the known side effects of corticosteroid therapy and were generally manageable within the study cohort.
Table 5.
Adverse events.
| Adverse events, n (%) | Statin (n = 52) | Non-statin (n = 52) | RR (95% CI) |
|---|---|---|---|
| liver dysfunction | 3 (5.8) | 1 (1.9) | 3 (0.32–27.91) |
| Stomach upset | 3 (5.8) | 4 (7.7) | 0.75 (0.18–3.19) |
| Weight gain | 2 (3.8) | 3 (5.8) | 0.67 (0.12–3.83) |
| New-onset hypertension | 2 (3.8) | 4 (7.7) | 0.50 (0.10–2.61) |
| New-onset hyperglycemia | 5 (9.6) | 4 (7.7) | 1.25 (0.36–4.40) |
Abbreviation: RR, relative risk; 95% CI, 95% confidence interval.
Discussion
Corticosteroids remain the cornerstone of the initial therapy for newly diagnosed ITP. However, the SR rate is suboptimal given to a high relapse rate and treatment resistance after discontinuation. 1 Additionally, corticosteroids often lead to metabolic disturbances, including hyperlipidemia, hyperglycemia, and hypertension, which complicates the management of patients with pre-existing metabolic disorders. 23 These challenges underscore the necessity for adjunctive therapies that not only improve treatment outcomes but also mitigate corticosteroid-induced metabolic disorders. In recent years, several novel therapeutic strategies for ITP have emerged, including FcRn inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, and BAFF inhibitors, which have demonstrated promising efficacy in patients with refractory or relapsed ITP.25–27 Collectively, these advances indicate that ITP management is evolving from broad immunosuppression toward more precise immune modulation. In the present study, adjunctive statin use in combination with corticosteroids was associated with a higher SR rate, suggesting that immunomodulation through lipid metabolic pathways may represent a novel therapeutic direction in ITP.
Hyperlipidemia is common in patients with autoimmune diseases, such as ITP, and may be further aggravated by corticosteroid therapy. 28 Dysregulated lipid metabolism has been implicated in the activation and differentiation of immune cells, contributing to the pathogenesis and progression of autoimmune diseases.29,30 Experimental evidence indicates that statins can improve bone marrow endothelial progenitor cell function and promote megakaryopoiesis, thereby enhancing platelet production in steroid-resistant ITP. 17 Recent retrospective evidence suggests that hyperlipidemia is common in ITP and is associated with more severe bleeding and treatment refractoriness, supporting the concept that disordered lipid metabolism may contribute to ITP pathogenesis and clinical heterogeneity. 13 Statins, beyond their established lipid-lowering effects, have demonstrated immunomodulatory properties and clinical benefits in various autoimmune and inflammatory diseases.31–33 These dual effects support the rationale for considering statins as adjunct therapy in ITP patients with hyperlipidemia. In this multicenter retrospective study, we evaluated the efficacy and safety of adding statins to corticosteroids in newly diagnosed ITP patients with pre-existing hyperlipidemia. We minimized potential confounding factors and ensured balanced baseline characteristics between the statin and non-statin groups using PSM. Our findings indicated that, while statins did not significantly increase the initial response rate of corticosteroid therapy at day 14, a trend toward a shorter time to response (TTR) was observed. More notably, the statin group achieved a higher SR rate at 6 months and longer DOR compared to the non-statin group. These results suggested that statins could improve long-term treatment outcomes in ITP patients with pre-existing hyperlipidemia.
The observed benefits of statins in this study might be attributed to their pleiotropic mechanisms. In addition to lipid-lowering, statins have been shown to modulate immune responses by inhibiting the NF-κB signaling pathway, downregulating the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), and restoring T-cell homeostasis.34,35 Recent studies also highlighted the impact of atorvastatin on bone marrow endothelial cell function and T-cell regulation in ITP, which might contribute to the prolonged remission observed in our cohort.14,18,36 Furthermore, improved lipid profiles in the statin group could also benefit immune regulation, as dyslipidemia has been found to be linked to chronic inflammation and immune dysregulation in autoimmune diseases.32,37 These findings were consistent with previous reports demonstrating the therapeutic potential of statins in SLE and RA.38,39 Nevertheless, the specific effects of statins on immune function in ITP patients still warrant further investigation.
Safety is a critical consideration when introducing adjunctive therapies. In our study, the combination of statins and corticosteroids was generally well tolerated, with no severe adverse events reported. Mild liver dysfunction was observed in 3 patients receiving statins but did not require treatment discontinuation. Muscle-related adverse effects, a concern with statin use, were not observed in our cohort. 40 These findings supported the favorable safety profile of statins in ITP patients with pre-existing hyperlipidemia, reinforcing their potential value as adjunctive therapy. It is notable that patients in the statin group had been receiving long-term statin therapy for lipid control and none discontinued statins during follow-up, the assessment of adverse events may therefore be subject to selection bias.
Limitations
Despite these promising results, several limitations should be acknowledged. As a retrospective study, although PSM and conditional logistic regression were used to minimize the effects of confounding factors, residual confounding cannot be completely ruled out. Statin users were generally older, with more comorbidities, and underwent more frequent follow-up, which could have influenced outcome assessment. A key limitation was the sample size, which was determined by patient availability rather than a formal power calculation. This might have left the study underpowered to detect smaller treatment effects and precluded subgroup analyses on specific statin types or dosages. Furthermore, data collection was constrained by the retrospective nature of the study. For instance, our lipid assessment was restricted to routine clinical panels, and we did not perform lipid sub-fraction analysis or functional tests (e.g., HDL particle function), which limits a deeper understanding of lipid metabolism in ITP. Pre-statin levels were also often unavailable, preventing a detailed analysis of lipid profile changes on ITP outcomes. The heterogeneity in statin type and potency across the cohort represented another significant limitation, as different statins might exert varied biological effects. Additionally, mild, statin-related adverse events may have been underreported, which is a common limitation in retrospective chart reviews. Therefore, our observational findings require validation through large-scale, prospective randomized controlled trials that standardize statin therapy. Such studies, complemented by mechanistic investigations into how statins modulate the bone marrow microenvironment and megakaryopoiesis, are essential to definitively establish their role in ITP treatment.
Conclusion
Our study showed that statin use in ITP patients with hyperlipidemia was associated with improved corticosteroid responses, suggesting that statins may serve as beneficial adjunct to corticosteroids in newly diagnosed ITP patients and support further evaluation of integrated immunometabolic treatment strategies, particularly in patients with coexisting metabolic disorders. These findings warrant further validation in larger, prospective cohorts.
Supplemental material
Supplemental material for Corticosteroids plus statins in patients with primary immune thrombocytopenia and hyperlipidemia: A multicenter retrospective cohort study by Xiran Hou, Yajing Zhao, Jian Chen, Lin Sun, Qiaofeng Dong, Changyong Yuan, Jian Lv, Shuang Liu, Na Gao, Ming Hou, Jun Peng, Zhenyu Yan, Xinguang Liu in Therapeutic Advances in Hematology
Acknowledgements
The authors thank all patients who participated in this study and acknowledge the efforts and contributions of doctors, nurses and hospital administration staff involved in the study.
Author contributions: Xiran Hou drafted the manuscript, collected the date and performed the statistical analyses. Yajing Zhao supervised the data analysis and revised the manuscript. Jian Chen, Lin Sun, Qiaofeng Dong, Changyong Yuan, Jian Lv, Shuang Liu and Na Gao collected the data. Xinguang Liu and Zhenyu Yan designed the study and provided statistical assistance. Ming Hou and Jun Peng supported funding this research. All authors reviewed the data, read and edited the manuscript.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of Zhejiang Province, Grant/Award Number: LQ24H080009; Natural Science Foundation of Shandong Province, Grant/Award Number: ZR2021MH132; National Natural Science Foundation of China, Grant/Award Number: 82170123 and 82300144; Young Taishan Scholar Foundation of Shandong Province, Grant/Award Number: tsqn202312325.
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Supplemental material: Supplemental material for this article is available online.
ORCID iDs
Zhenyu Yan https://orcid.org/0000-0002-3200-2380
Xinguang Liu https://orcid.org/0000-0002-1808-4498
Ethical considerations
This study was conducted in accordance with the Declaration of Helsinki. This retrospective multicenter study was approved by the Institutional Review Board (IRB) of Qilu Hospital of Shandong University (approval number KYLL-2020(KS)-362, date January 1, 2021).
Consent to participate
The participating centers acknowledged the IRB approval from the coordinating center according to their institutional requirements and contributed anonymized clinical information. Because the study involved only retrospective review of anonymized clinical data, the requirement for informed consent was waived by all the centers included.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.*
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material for Corticosteroids plus statins in patients with primary immune thrombocytopenia and hyperlipidemia: A multicenter retrospective cohort study by Xiran Hou, Yajing Zhao, Jian Chen, Lin Sun, Qiaofeng Dong, Changyong Yuan, Jian Lv, Shuang Liu, Na Gao, Ming Hou, Jun Peng, Zhenyu Yan, Xinguang Liu in Therapeutic Advances in Hematology
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.*