Glucocorticoid Therapy for Recurrent In-Stent Restenosis

Abstract

Background

Recurrent in-stent restenosis (RISR) remains a therapeutic challenge when conventional treatments show limited efficacy. This case series evaluated a prednisone-based therapeutic strategy in patients with unexplained RISR.

Methods

In this single-center prospective case series, 6 patients with RISR were included after exclusion of procedural failure, neoatherosclerosis, and systemic vasculitis by intracoronary imaging and laboratory testing. All patients had failed repeated revascularization and optimal medical therapy. Oral prednisone (0.5 mg/kg/d) was initiated and tapered monthly by 5 mg/d until a maintenance dose of 5-10 mg/d was achieved alongside guideline-directed therapy.

Results

Over a median follow-up of 4-years, 5 patients remained free from in-stent restenosis recurrence during treatment. One exhibited persistent in-stent restenosis but eventually achieved lesion stabilization after escalation to combined immunosuppressive therapy. Imaging demonstrated fibrotic neointimal hyperplasia without lipid-rich features. No serious steroid-related adverse events were observed.

Conclusions

Prednisone-based anti-inflammatory therapy may represent a potential strategy for the management of refractory RISR.

Take-Home Messages

Refractory RISR may represent an under-recognized inflammatory vascular process rather than purely mechanical failure. In selected patients who have exhausted conventional revascularization strategies, systemic anti-inflammatory therapy may offer a viable therapeutic alternative.

Graphical Abstract

Visual Summary.

Clinical Timeline of the 6 Study Patients

Each row represents an individual patient's clinical course from initial percutaneous coronary intervention to the most recent follow-up. Red stars indicate time points of ISR confirmed by coronary angiography, while black stars indicate angiographic evidence of stent patency. The darker bar represents the period of conventional medical therapy before prednisone initiation, and the corresponding lighter-colored bar indicates the duration of prednisone-based anti-inflammatory therapy. The arrow marks the initiation of intensified immunosuppressive therapy in case 2. ISR = in-stent restenosis.

Recurrent in-stent restenosis (RISR), defined as at least 2 episodes of restenosis within the same segment, remains a significant challenge in contemporary interventional cardiology, accounting for in approximately 20% of all cases with in-stent restenosis (ISR).¹ Traditionally, ISR was attributable to mechanical factors, such as stent underexpansion, malposition, or fracture, as well as patient-related factors including suboptimal control of lipids or glucose.² These cases can be effectively managed through optimized percutaneous coronary intervention (PCI) under intracoronary imaging guidance, coupled with intensive medical therapy to achieve risk-factor targets.³ However, a subset of patients derived little benefit from these strategies, suggesting alternative pathophysiologic mechanisms beyond conventional factors.

In such refractory cases, repeated PCI and coronary artery bypass grafting were often unavoidable, resulting in a vicious cycle of recurrent ischemia, repeated hospitalizations, myocardial infarction, and death. Beyond the clinical burden, RISR also imposed significant economic, psychological, and social strains, particularly in health care systems with limited resources for long-term management. The elusive mechanisms underlying RISR and the absence of targeted therapies contributed to its status as a persistent clinical dilemma.

Emerging evidence has implicated immune-mediated inflammation in the pathogenesis of ISR, suggesting that vascular injury responses may drive neointimal hyperplasia. However, many patients with RISR lack overt signs of immune dysfunction, complicating the identification of candidates for immunomodulatory therapy.

In this case series, we evaluated a novel combined approach incorporating prednisone, a potent anti-inflammatory agent, into standard RISR management. The primary aim was to assess the long-term effects of prednisone on immune modulation and restenosis recurrence, even in the absence of overt autoimmune disease. By targeting underlying inflammatory pathways, we sought to offer a novel strategy for improving outcomes in patients with refractory RISR.

Methods

Study design

This study was a single-center prospective exploratory case series analysis. The study design was approved by the Ethics Committee of Fuwai Hospital, and informed consent was received from the included participants.

Inclusion criteria

Inclusion criteria required that at least 1 coronary artery lesion met the following RISR criteria: 1) recurrent ISR: ≥2 episodes of ≥50% diameter stenosis within the stent or adjacent 5-mm segment, confirmed by coronary angiography (CAG); 2) exclusion of procedural factors: intravascular imaging (intravascular ultrasound [IVUS] or optical coherence tomography [OCT]) confirming adequate stent expansion and apposition; 3) no metal or polymer hypersensitivity: negative patch testing for metal allergies; 4) no neoatherosclerosis: intracoronary imaging showing no lipid-rich plaque or thin-cap fibroatheroma; and 5) no systemic autoimmune disease: absent clinical signs and negative laboratory markers (C-reactive protein, erythrocyte sedimentation rate, antinuclear antibodies, antineutrophil cytoplasmic antibodies). Only those patients who met all 5 of these criteria were considered eligible for study inclusion.

A total of 15 patients with RISR were initially identified and considered for prednisone-based anti-inflammatory therapy. Among them, 6 patients who adhered to the prescribed prednisone regimen and completed long-term follow-up were included in the final analysis; the remaining 9 were excluded owing to premature discontinuation or loss to follow-up.

Treatment strategy

The included patients received the following guideline-guided medical therapy for coronary artery disease:

• 1)Dual antiplatelet therapy: Patients who underwent reimplantation of a drug-eluting stent were treated with dual antiplatelet therapy (aspirin plus a P2Y12 receptor antagonist) for at least 12 months; patients who underwent drug-eluting ballon angioplasty received dual antiplatelet therapy for a minimum of 6 months.
• 2)Lipid-lowering therapy: Statin-based therapy of at least moderate intensity, with treatment titrated to achieve a target low-density lipoprotein cholesterol level of <1.4 mmol/L, in combination with or without PCSK9 inhibitors.
• 3)Optimization of antihypertensive and antidiabetic treatments to achieve guideline-recommended targets.

In addition, prednisone was added for its anti-inflammatory and immunomodulatory properties, at an initial dosage of 0.5 mg/kg/d, tapered monthly by 5 mg/d to a maintenance dosage of 5-10 mg/d. Tapering was individualized based on clinical response and tolerability.

Follow-up and endpoints

All patients were managed for 2 to 5 years (median: 4 years). The primary endpoint was major adverse cardiac and cerebrovascular events, defined as a composite of all-cause death, nonfatal myocardial infarction, stroke, and target lesion revascularization. Secondary endpoints included target vessel revascularization as well as other coronary revascularization procedures. Safety endpoints focused on adverse drug reactions related to prednisone and treatment discontinuation owing to intolerance or side effects.

Imaging and laboratory assessment

CAG was used to evaluate stenosis severity. OCT or IVUS was used to exclude neoatherosclerosis. Biochemical and immunological markers were monitored serially, particularly in patients with worsening risk factors or suggestive autoimmune features.

Results

Baseline characteristics

The 6 study patients with angiographically confirmed RISR (4 women, 2 men; mean age: 55 years) were enrolled between July 2018 and April 2023. Common risk factors included hypertension (4/6 patients), type 2 diabetes (4/6), and dyslipidemia (5/6), with median low-density lipoprotein cholesterol level of 1.64 mmol/L. One patient had a smoking history, and 2 had a family history of premature coronary artery disease (Table 1).

Table 1.

Baseline Information of the RISR Study Patients

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Demographics
Age, y	63	53	68	54	39	51
Sex	Female	Female	Male	Female	Male	Male
BMI, kg/m2	26.4	21.8	23.4	20.6	24.1	25.2
Smoking	—	—	—	+	—	—
Medical history
Diabetes, y	1	3	—	—	1	20
Hypertension, y	3	—	7	11	—	20
Dyslipidemia	2	11	3	9	8	5
Family history of CAD	+	—	—	+	—	—
MI	+	+	+	—	—	+
CABG	—	—	—	—	—	—
PAD	—	—	—	—	—	—
OSAS	—	—	—	—	—	—
Hypothyroidism, y	—	10	—	—	—	—
Allergy	—	—	—	—	—	—
Connective tissue disease	—	—	—	—	—	—
Antiplatelet drug resistance	—	—	—	—	—	—
Laboratory tests
HbA1C, %	6.7	6.3	8.1	7	6.8	7.5
TG, mmol/L	1.42	0.81	1.58	1.56	1.82	2.47
LDL, mmol/L	1.37	0.69	1.7	1.58	2.0	2.38
HDL, mmol/L	1.34	1.55	1.07	1.52	1.22	1.17
Lp(a) level, mg/dL	38	904	115	364	81	77.39
HsCRP, mg/dL	3.08	0.38	1.71	0.61	0.57	1.54
ESR, mm/h	13	29	7	12	4	5
ANA	—	—	—	—	—	—
ANCA	—	—	—	—	—	—
IgG4	—	—	—	—	—	—
ACL	—	—	—	—	—	—
Echocardiography
LVEF, %	62	60	63	64	56	60
Angiography
Target vessels	LAD, LCx	LAD, RCA	RCA	LAD, LCx	LAD, LCx	LAD
Number of ISR events	3	2	5	3	2	3
Stent underexpansion	—	—	—	—	—	—
Stent fracture	—	—	—	—	—	—
CTOs	—	+	+	+	—	+

ACL = anticardiolipin antibodies; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; BMI = body mass index; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CTO = chronic total occlusion; DES = drug-eluting stent; ESR = erythrocyte sedimentation rate; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; IgG4 = immunoglobulin G4; LAD = left anterior descending artery; LCx = left circumflex artery; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); LVEF = left ventricular ejection fraction; MI = myocardial infarction; OSAS = obstructive sleep apnea syndrome; PAD = peripheral artery disease; RCA = right coronary artery; TG = triglyceride.

All patients presented with multivessel coronary artery disease at baseline, with frequent involvement of the left anterior descending artery (LAD; 5/6 patients). Severe stenosis (≥90%) was universal in all patients, and chronic total occlusions were present in 4 patients (66.7%). Initial revascularization was performed using drug-eluting stents, with a median of 3 stents (range: 1-5) per patient, targeting complex lesions such as ostial to mid LAD occlusion and diffuse right coronary artery disease.

RISR episodes occurred frequently, with a minimum of 2 episodes per patient, and approximately 25% of these events presented as acute coronary syndrome. The average interval between ISR diagnosis and repeat intervention was 11 months.

Additionally, all patients tested negative for autoimmune serological markers, including antinuclear antibodies, antineutrophil cytoplasmic antibodies, immunoglobulin G4, and other connective tissue disease–related antibodies. Inflammatory biomarkers such as high-sensitivity C-reactive protein and erythrocyte sedimentation rate were generally within normal limits, with only mild elevations observed in a few cases. These findings effectively ruled out systemic vasculitis or connective tissue diseases, although localized coronary vascular inflammation could not be excluded. Furthermore, all 6 patients had negative results on patch testing for metal and polymer hypersensitivity, excluding allergic reactions to stent components as a potential cause.

Detailed imaging evaluations were performed in all patients at baseline. CAG confirmed ISR lesion location and severity, and IVUS and OCT revealed diffuse neointimal hyperplasia and ruled out procedural factors such as stent underexpansion, malapposition, or neoatherosclerosis (Figures 1, 2, 3, 4, 5, and 6). These 6 patients were diagnosed with recurrent or refractory ISR of unknown etiology and were subsequently included in the study.

Figure 1.

Coronary Angiography and Intracoronary Imaging Findings of Patient 1

(A) Second ISR episode: CAG showed 95% ISR in the LCx; (B) revascularization was successfully performed using a DCB. (C) Third ISR episode (3 months later): CAG showed 99% ISR in the LCx; (D) IVUS demonstrated predominantly fibrotic neointima, (E) OCT confirmed fibroproliferative tissue composition; (F) revascularization was successfully performed using a DCB. Low-dose prednisone was initiated postprocedure. (G) Follow-up CAG at 12 months showed a patent LCx stent with no evidence of restenosis; anti-inflammatory therapy was continued. (H) At the 7-month follow-up, coronary CTA showed no ISR in the (I) LAD or (J) LCx stents. (K) Ten months after discontinuation of prednisone, CAG demonstrated 90% ISR in the LCx. CAG = coronary angiography; CTA = computed tomography angiography; DCB = drug-coated balloon; ISR = in-stent restenosis; IVUS = intravascular ultrasound; OCT = optical coherence tomography.

Figure 2.

Coronary Angiography and Intracoronary Imaging Findings of Patient 2

(A) First ISR episode: CAG revealed 100% in-stent occlusion in the mid-RCA to PDA; (B) OCT showed a homogeneous fibrotic neointimal pattern, and (C) revascularization was successfully performed using a DCB. (D) First ISR episode: CAG showed 100% ISR in the proximal LAD; (E) OCT revealed a fibrotic neointimal pattern, and (F) revascularization was successfully performed using a DCB. (G) Second ISR episode (10 months later): CAG showed 100% ISR in the LAD; (H) IVUS indicated fibrotic tissue proliferation within the stent; (I) the patient received a single new DES and 3 DCBs, and revascularization was successfully performed. Triple anti-inflammatory therapy with prednisone, tocilizumab, and tacrolimus was initiated postprocedure. (J) Fourth ISR episode (10 months later): CAG showed 100% in-stent occlusion in the LAD; (K) OCT demonstrated predominantly fibrotic neointima with minor lipid components, and (L) revascularization was successfully performed using a DCB. (M) Fifth ISR episode (14 months later): CAG showed 80% ISR in the mid-LAD, with notable improvement in lesion severity; (N) IVUS confirmed neointima consisting mainly of fibrous tissue with some lipid elements; (O) revascularization was successfully performed using a DCB, and the anti-inflammatory regimen was adjusted to prednisone, mycophenolate mofetil, and tacrolimus. (P) Follow-up at 13 months post-treatment showed patent LAD stents with no evidence of restenosis. DES = drug-eluting stent; PDA = posterior descending artery; RCA = right coronary artery; other abbreviations as in Figure 1.

Figure 3.

Coronary Angiography and Intracoronary Imaging Findings of Patient 3

(A) Fourth ISR episode (6 months after the previous episode): CAG showed 99% ISR at the RCA stent edge; (B) revascularization was successfully performed using a DES. (C) Fifth ISR episode (11 months later): CAG showed 95% ISR in the proximal-to-mid RCA; (D) revascularization was successfully performed using 2 DCBs. Prednisone was initiated postprocedure. DES = drug-eluting stent; RCA = right coronary artery; other abbreviations as in Figure 1.

Figure 4.

Coronary Angiography and Intracoronary Imaging Findings of Patient 4

(A) Second ISR episode (12 months after the previous episode): CAG showed 100% ISR in the LAD; (B) revascularization was successfully performed using 2 DCBs. (C) Third ISR episode (12 months later): CAG showed 100% ISR in the LAD; (D) IVUS revealed fibrotic neointima; (E) revascularization was successfully performed using a DCB. Prednisone was initiated postprocedure. Abbreviations as in Figure 1.

Figure 5.

Coronary Angiography and Intracoronary Imaging Findings of Patient 5

(A) Second ISR episode (4 years after the previous episode): CAG showed 90% ISR in the LAD; (B) IVUS revealed fibrotic neointima; (C) revascularization was successfully performed using a DCB. (D) Second ISR episode (4 years later): CAG showed 95% ISR in the RCA and 80% stenosis in the PLA; (E) revascularization was successfully performed using 2 DCBs. (F) Third ISR episode (3 years later): CAG showed 90% ISR in the LAD. PLA = posterolateral artery; RCA = right coronary artery; other abbreviations as in Figure 1.

Figure 6.

Coronary Angiography and Intracoronary Imaging Findings of Patient 6

(A) Third ISR episode (7 months after the previous episode): CAG showed 90% ISR at the distal edge of the LAD stent; (B) IVUS revealed dense fibrotic tissue, and (C) revascularization was successfully performed using a DCB. (D) Follow-up at 20 months post-treatment showed patent LAD stents with no evidence of restenosis. Abbreviations as in Figure 1.

The detailed baseline data including demographics, lesion characteristics, and procedural history are listed in Supplemental Appendix.

Interventions

Within 48 hours of successful revascularization, all patients received systemic anti-inflammatory therapy with oral prednisone at an initial dosage of 0.5 mg/kg/d. This was followed by a standardized tapering protocol, with dose reductions of 5 mg/d per month until a maintenance dosage of 5–10 mg/d was achieved, tailored to individual body weight and clinical tolerance.

Patient 1 maintained prednisone therapy for a total duration of 50 months before discontinuation. Patient 2 discontinued prednisone after 1 month because of lung cancer surgery; during subsequent ISR recurrences, immunosuppressive therapy was escalated to triple regimen with prednisone, tocilizumab (an IL-6 receptor antagonist), and tacrolimus, followed by modification to a maintenance regimen of prednisone, mycophenolate mofetil, and tacrolimus. Patients 3, 4, and 6 continued low-dose prednisone treatment throughout the follow-up period without discontinuation. Patient 5 discontinued prednisone after 6 months given poor glycemic control and experienced late recurrence of ISR. No significant adverse drug reactions attributable to prednisone were reported in the remaining 5 patients.

Clinical outcomes

During prednisone treatment, 5 out of the 6 patients (patients 1, 3, 4, 5, and 6; 66.7%) remained free of ISR. Patient 1 underwent follow-up CAG at 12 months, which demonstrated patent stents in both the LAD and the left circumflex artery without significant restenosis (Figure 1G), and 7 months later, coronary computed tomography angiography similarly showed no evidence of ISR (Figures 1H to 1J). Patients 3, 4, and 5 remained free of cardiovascular events throughout the follow-up period. Patient 6 underwent follow-up CAG at 15 months, which revealed no restenosis in the LAD stent (Figure 6D).

Patient 2 experienced ISR recurrence 8 months after discontinuation of prednisone therapy. After initiation of the triple immunosuppressive regimen (prednisone, tocilizumab, and tacrolimus), 2 additional ISR episodes occurred, both presenting as complete (100%) LAD occlusion, with an average interval of 7 months. Notably, at the third ISR episode (14 months after triple immunotherapy), the severity of LAD restenosis was attenuated, manifesting as 80% stenosis rather than total occlusion (Figure 2M). Subsequently, the immunosuppressive regimen was modified to prednisone, mycophenolate mofetil, and tacrolimus, and follow-up CAG at 13 months demonstrated persistent stent patency (Figure 2P).

Of note, 2 patients experienced ISR recurrence after discontinuation of prednisone. Patient 1 developed non-ST-segment elevation myocardial infarction 10 months after self-discontinuing prednisone, with angiography revealing 99% ISR in the left circumflex artery (Figure 1K), and patient 5, who had discontinued prednisone after 6 months given poor glycemic control, experienced ISR recurrence 3 years later (Figure 5F).

Discussion

RISR remains a therapeutic challenge, particularly in patients with repeated recurrences despite optimal PCI and guideline-guided medical therapy. Reported recurrence rates reach 20% at 1 year and exceed 50% within 2 years.¹ In this exploratory case series, we evaluated the efficacy and safety of low-dose prednisone–based anti-inflammatory regimens in 6 patients with RISR, each having undergone at least 3 revascularization procedures at baseline. Encouragingly, 5 of the patients showed favorable outcomes during prednisone therapy, with no recurrence of ISR. One patient (patient 2) demonstrated a more complex clinical course and was therefore analyzed separately rather than included in the pooled efficacy interpretations. Overall, these observations suggest a potential therapeutic role for systemic anti-inflammatory therapy in selected patients with refractory RISR and further highlight the contribution of immune-mediated vascular inflammation to disease persistence.

Clinical profile of RISR

In this cohort, RISR frequently manifested as symptom-driven events, with a considerable proportion (approximately 25%) presenting as acute coronary syndrome, consistent with previous reports.⁴ The LAD was the most commonly involved vessel, and the target lesions predominantly exhibited critical luminal stenosis. The median interval between ISR episodes tended to be less than 12 months.

These refractory RISR cases could not be explained by the conventional mechanisms of ISR. And in our cohort, autoimmune testing was negative in all patients, and patch testing for stent allergies also yielded negative results. Inflammatory biomarkers such as high-sensitivity C-reactive protein and erythrocyte sedimentation rate were not consistently elevated. This aligns with recent evidence indicating that these biomarkers may lack diagnostic specificity in the context of RISR. Intravascular imaging (IVUS, OCT) revealed diffuse neointimal hyperplasia characterized predominantly by fibrotic tissue without features of lipid-rich plaque, ruling out neoatherosclerosis as the dominant pathology.⁵ In patient 2, lipoprotein(a) was markedly elevated (904 mg/dL), a factor associated with adverse ISR outcomes. However, serial intracoronary imaging consistently demonstrated fibrotic neointimal hyperplasia without lipid-rich features, suggesting that lipid-driven neoatherosclerosis was unlikely to be the dominant mechanism.

Taken together, these findings suggest that RISR may be driven by a persistent, localized inflammatory process, which leads to aggressive neointimal hyperplasia/proliferation, rather than classic atherosclerotic progression or procedural failure.

Anti-inflammatory therapy strategy

Prednisone has shown well-established efficacy in treating vascular inflammatory conditions. Early randomized controlled trials in the era of bare-metal stents have demonstrated that oral prednisone can significantly reduce ISR rates.⁶ With the advent of mTOR-inhibiting drug-eluting stents, ISR management has largely focused on local antiproliferative strategies rather than systemic inflammatory modulation. This shift was driven less by lack of biological rationale and more by concerns regarding systemic toxicity when anti-inflammatory therapies are applied broadly.

Despite the widespread use of antiproliferative drug-eluting stents, emerging cases have described recurrent ISR characterized by intense tracer uptake on positron emission tomography/computed tomography, suggesting isolated coronary arteritis, which may benefit from immunomodulatory therapy.⁷ These reports provided important evidence for the potential role of corticosteroid-based immunomodulatory therapy in managing RISR with suspected inflammatory etiology.

The present study specifically targeted patients with refractory RISR who had exhausted conventional mechanical and local pharmacological options, a setting in which the risk-benefit balance of systemic anti-inflammatory therapy may be more acceptable. The present study addressed refractory RISR by using a low-dose, long-term prednisone regimen following the protocol developed by Zhang et al⁸ at Fuwai Hospital, which has demonstrated both safety and efficacy in Takayasu arteritis. In patients with an inadequate response to prednisone monotherapy, the addition of immunosuppressive agents such as tacrolimus or tocilizumab may be beneficial. Notably, patient 2 required stepwise escalation beyond prednisone monotherapy, including additional immunosuppressive agents, and was therefore not considered representative of glucocorticoid efficacy alone. However, the marked attenuation of ISR progression after intensified anti-inflammatory therapy in this patient suggests that RISR may remain responsive to broader immunomodulatory strategies when glucocorticoid monotherapy proves insufficient. This observation reinforced the concept that RISR was closely linked to inflammatory pathways, while emphasizing that anti-inflammatory treatment should be individualized, with careful escalation and dynamic adjustment based on therapeutic response and patient-specific risk profiles. Furthermore, given the observed recurrence of ISR after prednisone withdrawal, our findings illustrate that selected RISR patients may benefit from prolonged low-dose maintenance therapy with extended follow-up to ensure durability of response.

Taken together, these findings suggest that while systemic anti-inflammatory therapy is not appropriate for routine ISR management, it may represent a tolerable and potentially effective strategy in a narrowly defined subset of patients with refractory RISR.

Safety considerations

Before initiating prednisone, contraindications must be carefully reviewed, and adverse effects should be closely monitored during treatment. Adjunctive prophylactic measures, including vitamin D and calcium supplementation and proton pump inhibitors when appropriate, were routinely considered to mitigate steroid-related complications.

Glycemic control requires particular attention, as illustrated by patient 5, who developed poor glycemic control during therapy, highlighting the need to balance inflammation suppression with metabolic risks. Hyperglycemia can exacerbate endothelial dysfunction and promote smooth muscle proliferation, potentially worsening ISR. Therefore, immunomodulatory regimens for RISR should be individualized, with the goal of minimizing the maintenance dose of prednisone once clinical remission is achieved.

In addition, the long-term safety of systemic immunosuppression warrants further investigation, particularly regarding infection, metabolic disturbances, and drug interactions.

Future perspectives

Accumulating evidence suggests that RISR may reflect an immunological component and, in certain cases, could represent an initial manifestation of a systemic inflammatory condition prior to overt multisystem involvement. For instance, coronary artery involvement was observed in approximately 10% to 45% of patients with Takayasu arteritis, highlighting the potential for early, isolated coronary inflammation.⁹ However, the current diagnostic approach was limited by the availability and sensitivity of conventional serological markers, which often delays definitive diagnosis. This underscores the urgent need to identify novel immune biomarkers to facilitate earlier detection and intervention in patients with suspected inflammation-mediated RISR. Moreover, larger prospective cohorts with extended follow-up durations are warranted to validate the efficacy and long-term safety of low-dose prednisone and adjunctive immunosuppressive therapies in this high-risk population. Our team is currently conducting a prospective, randomized controlled trial (NCT06090890).¹⁰

Limitations

This was a small, single-center case series without randomization or a control group. Only 40% of screened patients completed long-term follow-up, which may introduce selection bias. Additionally, although the potential long-term risks of glucocorticoid therapy, including bone mineral density loss, infection risk, and adrenal suppression, were recognized, these safety endpoints were not systematically or prospectively assessed in this exploratory case series. Finally, histological confirmation of inflammation was not available, limiting mechanistic inference.

Conclusions

This study proposes a novel anti-inflammatory strategy for refractory RISR after excluding mechanical, metabolic, and hypersensitivity causes. Low-dose prednisone, alone or with other immunosuppressants, may provide clinical benefit in selected patients when combined with standard revascularization and medical therapy.

Funding Support and Author Disclosures

This work was supported by the National Key Research and Development Program of China (No. 2022YFC2009700, 2022YFC2009706), Foundation for Clinical and Translational Medical Research, Central Public Welfare Research of Chinese Academy of Medical Sciences (No. 2019xk320061, 2022-I2M-C&T-B-050), Natural Science Foundation of Beijing Municipality (No. 7222139, 26G10379), Foundation for Clinical research of central high-level hospitals (No. 2023-GSP-GG-32), Beijing Research-Oriented Ward Excellence Clinical Research Program (No. BRWEP2024W012060111), High-level Research Special Project of the National Clinical Research Center for Cardiovascular Diseases of Beijing Anzhen Hospital (No. 2025AZB5003, 2024AZB1004), and Foundation for Beijing Municipal Administration of Hospitals Incubating Program (No. PZ2020005). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •Refractory recurrent in-stent restenosis may represent an under-recognized inflammatory vascular process rather than purely mechanical failure.
• •In selected patients who have exhausted conventional revascularization strategies, systemic anti-inflammatory therapy may offer a viable therapeutic alternative.