Short- and longevity outcome of cyclosporin rescue therapy in severe ulcerative colitis refractory to intravenous corticosteroid treatment

Abstract

Background:

Many patients with severe ulcerative colitis (UC) fail to respond to first-line corticosteroids and require second-line rescue therapy with cyclosporin (CsA) to avoid colectomy.

Objectives:

To assess the short- and long-term effectiveness and safety of CsA therapy.

Design:

A single-center, retrospective study was conducted, including patients who received IV CsA therapy for severe, steroid-refractory UC.

Methods:

Data on therapeutic response and adverse events (AEs) were reported. The Kaplan-Meier method was used to estimate colectomy-free survival rates. The incidence of inflammatory bowel disease flare-ups and the use of advanced therapies after CsA discontinuation were also assessed. Regression analyses were performed to identify predictors for therapeutic response, colectomy, and AEs with CsA.

Results:

A total of 92 UC patients (54.4% male, mean age: 40.0 ± 14.0 years) were included with the median follow-up time of 14 years (IQR: 7–18). Clinical response was achieved in 88.0%, and clinical remission was observed in 23.9% of patients after the median 6-day (IQR: 7–5) IV phase. A total of 40.7% of responders experienced clinical remission, whereas 13.6% had endoscopic remission at the time of CsA withdrawal (median after 5 months of therapy). Patients receiving concomitant immunomodulators were more likely to achieve clinical remission with CsA (p = 0.002; OR: 6.4). After CsA discontinuation, 23.5% of patients relapsed within 6 months, while 59.3% of patients were started on biologics. The probability of colectomy-free survival was 74.7%, 62.6%, 57.1%, and 45.6% at 1, 3, 5, and 14 years after CsA initiation. AEs were reported in 53.3% of patients, mainly hyperlipidaemia, hypertension, and infections. Hypoalbuminaemia (<35 g/L) at treatment initiation increased the risk of AEs (p = 0.03; OR: 0.4), whereas the occurrence of AEs was not associated with concomitant immunomodulator use (p = 0.9).

Conclusion:

CsA may be a potent therapeutic option to induce remission in steroid-refractory, severely active UC, and its effectiveness may be enhanced by the concomitant use of immunomodulators, without compromising safety.

Keywords

cyclosporine rescue therapy ulcerative colitis

Introduction

About 15%–25% of the ulcerative colitis (UC) patients experience a severe relapse throughout their disease course, which in one third of cases eventually leads to a colectomy.^1–3 For decades, corticosteroids have been the first-line therapy in patients with severe UC; however, 30%–40% of the patients fail to respond and require second-line rescue treatment with cyclosporin (CsA) or infliximab (IFX) to avoid colectomy and improve long-term outcomes.^4,5

For years, CsA was the only option to rapidly induce remission for severe, steroid-refractory UC patients.^6,7 Previouly reported short- and long-term outcomes with CsA have shown high variability (with a median follow-up up to 6.6 years), with 74%–91% of patients avoiding colectomy in the short term, while 45%–62% of patients have avoided surgery in the long run.^6–17

It is generally agreed upon that CsA therapy can cause substantial side effects, including opportunistic infections, hypertension, neuro-, nephro-, and hepatotoxicity, which can occur in up to 17% of patients during treatment.^18–20 Treatment-related minor and major complications, and the need for tight patient monitoring with frequent serum level measurements, limit the widespread use of CsA, which may result in prioritizing IFX for severe steroid-refractory UC.²¹ The efficacy of IFX has been extensively studied in acute severe UC.^22,23 Even though the largest randomized controlled trials (RCTs) have not demonstrated a significant difference in the efficacy and safety with IFX and CsA in acute severe UC patients,^24–26 non-RCT studies suggest that IFX is associated with better therapeutic response and lower risk of colectomy at 12 months.²⁷ To date, there is limited data on the use of new biologics and small-molecule agents in the treatment of acute severe UC (ASUC), however, studies suggest that tofacitinib may be also an effective option in acute severe UC.^28–30 Notably, Atia et al.³¹ found that even advanced therapies were not able to significantly reduce the colectomy rate in UC.

In the era of biologicals and small molecules, data on whether there is still a role in the therapeutic algorithm for CsA in severe steroid-refractory UC are conflicting. Given the lack of longevity follow-up data (>5 years) on UC patients who have successfully achieved remission with CsA therapy, we aimed to assess the short- and long-term effectiveness and safety of CsA therapy in steroid-refractory severe UC.

Materials and methods

Study design and settings

We conducted a single-center, retrospective observational cohort study including all patients who received IV CsA therapy for severe steroid-refractory UC between 01/01/2001 and 01/02/2024. Due to administrative issues, it was not possible to identify patients treated with IV CsA before the year 2001. Patients who are currently receiving IV CsA therapy and those who do not have at least 6 months of follow-up after CsA initiation, were excluded from the study. The required data were retrieved from the local medical record system and entered into a purpose-designed database. The follow-up time was estimated from the initiation of the CsA to the last UC-related medical appointment.

Participants

As per our inclusion criteria, only diagnosed UC patients (based on clinical, biochemical, endoscopic, and histological findings) ⩾18 years of age were considered.³² The disease phenotype was defined according to the Montreal classification.³³ Clinical and endoscopic disease activity was evaluated using the Mayo endoscopic subscore (eMayo) and the partial Mayo score (pMayo).³⁴ The indication of CsA therapy was severe UC, defined as a pMayo score of ⩾7 and an eMayo score of ⩾2. All participants were treated unsuccessfully with 1 mg/kg/day methylprednisolone IV for 3–7 days before CsA as first-line rescue therapy. Due to refractoriness to corticosteroids, patients received a median 3 mg/kg/day (IQR: 2–4 mg/kg/day) CsA IV for 5–7 days for second- or third-line (following ineffectiveness or loss of response to second-line IFX) rescue treatment. IV CsA was followed by oral treatment in case of clinical response (defined as a decrease in pMayo from baseline points). Serum CsA levels were monitored to achieve and maintain a trough serum level of 150–300 ng/L. All patients went through a comprehensive screening to rule out the most common infections and autoimmune diseases prior to the initiation of CsA treatment. In the early 2000s, chest X-rays were the only method available for tuberculosis (TB) screening, but since the late 2010s, the Quantiferon TB test has been added to the screening protocol.

Data collection

The demographic data and clinical characteristics included date of birth, sex, smoking habit, date of UC diagnosis, and disease duration. Age, disease extent, and severity were observed at diagnosis, at the time of CsA initiation, and during follow-up. The need for inflammatory bowel disease (IBD)-related hospitalizations and the therapeutic agents used prior to CsA therapy were also reported. The duration of CsA therapy and the reason for treatment discontinuation were recorded, in addition to laboratory parameters (C-reactive protein (CRP), serum albumin), body mass index (BMI), at the time of treatment initiation (within 1 week). Kidney and liver function were closely monitored during CsA therapy. The therapeutic response to CsA was also recorded after the IV phase, together with the value of pMayo and laboratory parameters. Primary failure was defined as an insufficient response to IV CsA therapy. Loss of response was reported in patients who responded to IV CsA therapy but subsequently lost response during maintenance treatment with oral CsA. The type, severity, and reversibility of adverse events (AEs) associated with CsA therapy were also documented. Use of concomitant immunomodulators (azathioprine, 6-mercaptopurine), corticosteroids (methylprednisolone, budenoside), and biological or small-molecule therapy was also noted. The maintenance therapy after the withdrawal of CsA was also documented. Furthermore, the date and indication of colectomy, and postoperative complications within 90 days were also assessed. Relapse was defined as an increase in IBD-related treatment, whether it was a change in drug dosage or in therapeutic regimen, or the initiation of corticosteroids, hospitalization, or the need for surgical intervention.

Outcomes

The primary outcome was to assess the rate of clinical response and remission (defined as a pMayo score ⩽ 2 with a rectal bleeding subscore of 0) to IV CsA therapy in steroid-refractory severe UC. The secondary outcome was to observe the rate of clinical remission, the rate of colectomy among responders with per os CsA therapy, as well as the rate of colectomy-free survival after CsA initiation. Furthermore, we aimed to identify factors predictive of therapeutic response to IV and oral CsA, along with predictors of colectomy and AEs during CsA therapy.

Statistical methods

All statistical analysis was carried out using the program Statistical Package for the Social Sciences (SPSS; version 29.0 for Windows, IBM Corp., Armonk, NY, USA). Descriptive statistical analysis was presented as median with interquartile range (IQR) or mean with standard deviation (SD) for continuous variables. Categorical variables were summarized using frequency and percentage. The chi-square test or Fisher’s exact test was used to determine the associations between patient groups and categorical variables. Kaplan-Meier analyses were performed to assess the rates of colectomy-free survival. Uni- and multivariable logistic regression models with forward stepwise selection were used to investigate the factors influencing therapeutic response to CsA, the occurrence of AEs, and the need for colectomy. First, we developed an univariable model using clinically relevant factors, and then variables with a p-value ⩽ 0.15 were entered into the multivariable analysis. Hosmer-Lemeshow goodness of fit test was created to determine the performance of the final model, and the value of Nagelkerke R² was also reported. A p-Value less than 0.05 was considered significant. Incomplete or missing data were not imputed. All patients who achieved remission were also counted as responders.

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.³⁵

Results

During the study period, 104 UC patients received CsA therapy for severe disease activity at our tertiary referral center (Figure 1).

Figure 1.

Flowchart showing patient disposition throughout the study period. Colectomies marked in blue occurred during CsA therapy, while colectomies highlighted with yellow occurred after CsA discontinuation.

Patient characteristics

Due to the exclusion criteria, we eventually enrolled a total of 92 patients (Figure 1; 54.4% male; mean age: 55 ± 14.5 years) in the study, with a median of 14 years (IQR: 7–18; mean: 12.4 ± 6.4 years) of follow-up.

At the start of CsA, 68.5% of the patients had extensive UC, mainly (83.7%) showing signs of severe endoscopic activity. The mean pMayo at the start of CsA therapy was 8 points (±0.99 points). Concomitant IMT was observed in 58.7% (n = 54) of patients, of which 44.4% (n = 24) patients were started on the medication in combination with CsA. All patients began to taper off systemic corticosteroids once CsA was initiated (Table 1). None of the patients involved in the study received prophylactic treatment for Pneumocystis jirovecii.

Table 1.

Baseline characteristics of the 92 UC patients.

Demographic characteristics (n = 92)
Age (years; mean ± SD, median)	55 ± 14.5, 53.5
Male	50 (54.4%)
Smoking habits (n,%)
Never smoked	62 (67.4%)
Former smoker	22 (23.9%)
Active smoker	8 (8.7%)
Follow-up (years; mean ± SD, median)	12.4 ± 6.4, 14.0
Age at diagnosis (years; mean ± SD, median)	34.0 ± 12.9, 31.0
Age at the time of CsA initiation (years; mean ± SD, median)	40.0 ± 14.0, 39.0
Disease duration at the time of CsA initiation (years; mean ± SD, median)	6.0 ± 6.9, 4.0
Extraintestinal manifestation (n,%)
Hepatobiliary	2 (2.2%)
Dermatologic	3 (3.3%)
Therapeutic agent(s) used as rescue therapy (n,%)
Corticosteroid	81 (85.9%)
Corticosteroid and Infliximab	13 (14.1%)
Prior biological or small-molecule treatment (n = 13; 14.1%)
1 line of therapy	10 (84.6%)
2 lines of therapy	3 (15.4%)
Prior use of immunomodulators (AZA, 6-MP) (n,%)	57 (61.9%)
Montreal classification at diagnosis (n,%)
Proctitis	2 (2.2%)
Left-sided colitis	27 (29.3%)
Extensive colitis	63 (68.5%)
eMayo score at the time of CsA therapy
eMayo 2	15 (16.3%)
eMayo 3	77 (83.7%)
BMI at CsA initiation (mean ± SD, median)	23.8 ± 4.8, 23.0
pMayo at CsA initiation (mean ± SD, median)	8.0 ± 0.99, 8.0
Serum albumin level at CsA initiation (mean ± SD, median)	33.7 ± 7.7, 34.0
Serum CRP level at CsA initiation (mean ± SD, median)	64.7 ± 62.8, 43.9

6-MP, 6-mercaptopurin; AZA, azathioprin; BMI, body mass index; CRP, C-reactive protein; CsA, cyclosporin; n, number of patients; pMayo, partial Mayo score; SD, standard deviation; UC, ulcerative colitis.

Response to cyclosporin therapy

Clinical response was achieved in 88.0% (81/92) of patients, and clinical remission was observed in 23.9% (22/92) of patients after the IV phase. Based on logistic regression analysis (included as Supplemental Material, Table S1), no predictors were found for the response to IV CsA.

During oral CsA therapy (81/92 patients; mean: 9.0 ± 11.5 months; median: 5.0 months) relapse rate was 41.9% (34/81; 5.4 months ± 7.2 months after the start of CsA), whereas 40.7% (33/81) of patients achieved or maintained remission. Given the results of the multivariable logistic regression model (presented as Supplemental Material; Table S2), concomitant IMT was shown to be the only predictor of remission with oral CsA therapy (Table 2; p = 0.002; OR: 6.41; 95% CI: 1.92, 21.36).

Table 2.

Predictors of various outcomes based on uni-and multivariable logistic regression models.

Outcomes	Variables	Sig.	OR	95% CI
Remission with oral CsA therapy	Concomitant immunomodulator use	0.002	6.41	1.92	21.36
Colectomy during CsA therapy	Response to IV CsA	0.003	1.11	0.03	0.48
Adverse event during CsA therapy	Normal (>35 g/L) serum albumin level at the time of CsA initiation	0.03	0.36	0.14	0.91

95%CI, 95% confidence interval; CsA, cyclosporin; IV, intravenous; OR, odds ratio; sig, significance level.

Cyclosporin therapy discontinuation

In 12.0% (11/92) of patients, CsA therapy was discontinued due to primary failure, which was established in all cases during or after the IV phase of CsA. Loss of response was detected in 38.0% (35/92) of patients. CsA was withdrawn due to adverse events in 14.1% (13/92) of patients. A total of 40.7% (33/81) of patients were in clinical remission at the time of CsA discontinuation. At the end of CsA therapy (within 1 week), a total of 55/81 patients underwent colonoscopy, during which endoscopic remission was detected in 20% of patients (11/55; 13.6% based on intention-to-treat analysis).

Biological therapy was started immediately in 36.4% (4/11) of non-responders, and in 59.3% (48/81) of responders after an average of 7.2 (±6.7) months from the start of CsA. However, in the latter group of patients, 14.8% (12/81) required more than one line of biological or small-molecule therapy to maintain remission and avoid colectomy after CsA treatment. Immunomodulators were used in 54 out of 92 responders (58.6%) following CsA discontinuation, as maintenance therapy (n = 26; 48.2%) or as part of combination therapy (Figure 1).

Relapse was observed in 23.5% (19/81) of responders within 6 months of CsA withdrawal, with an average of 4.6 (±3.1 months) months after discontinuation. In 73.7% (14/19) of hospitalized patients needed treatment modification, including six patients requiring colectomy for ASUC.

Colectomy rates and predictors

The probability of colectomy-free survival was 74.7%, 62.6%, 57.1% and 45.6% at 1, 3, 5, and 14 years after CsA initiation (Figure 2).

Figure 2.

The probability of colectomy-free survival up to 168 months (14 years) after CsA therapy initiation.

During CsA therapy, 21.7% (20/92; seven patients were non-responders to IV CsA) of patients underwent colectomy on average 3.7 (±2.9 months) months after initiation, primarily due to ASUC (n = 14; 70.0%). Postoperative complications were reported in 25.0% of the patients (5/20; fistulas and abscesses: 4/5; subileus: 1/5), and 11/20 (55.0%) patients developed pouchitis (54.5% with moderate severity) during the follow-up period. Based on the results of multivariable regression analysis (included as Supplemental Material; Table S3), nonresponse to IV CsA was the only predictor of colectomy during CsA therapy (Table 2; p = 0.003; OR: 1.11; 95% CI: 0.03, 0.48).

After CsA discontinuation, 36.1% (26/72) of patients had colectomy on average 43.7 months (±52.5 months; median: 22.0 months, mainly due to chronically active, refractory UC (n = 17; 65.4%). Among the patients who were in remission at the time of CsA discontinuation, 21.2% (7/33) still required colectomy subsequently (53.3 ± 47.6 months after CsA withdrawal). In contrast, in patients who responded to IV CsA but were unable to achieve or maintain remission with oral CsA, surgery was inevitable in more than a third of cases (37.5%; on average, 41.3 ± 56.4 months after CsA). Postoperative complications were observed in 30.8% (n = 8; haematochesia: 3/8; subileus: 1/8; fistulas and abscess: 4/8) of patients, while pouchitis was present in 57.7% (15/26) of patients, usually with mild symptoms (60.0%).

Overall, 50.0% (46/92) of the total patient population and 51.9% (42/81) of CsA responders avoided colectomy during the follow-up period.

Adverse events

CsA-associated AEs were reported in 53.3% (n = 49) of patients on a total of 82 occasions (0.89 per patient), summarized in Table 3. During the course of treatment, the following infections occurred, with four cases requiring hospitalization: TB pneumonia, Clotridioides difficile colitis, Campylobacter jejuni enteritis, Salmonella enterocolitis, Cytomegalovirus colitis, infectious mononucleosis, and oropharyngeal candidiasis. Impaired kidney function was detected in two patients, both with a 10%–20% increase in serum creatinine without any other prerenal, renal, or postrenal cause. In 13.0% (12/92) of patients, dose reduction was implemented as a result of AE. Treatment discontinuation was inevitable in three patients due to infection (Cytomegalovirus colitis, TB pneumonia, oropharyngeal candidiasis), in one patient due to epilepsy, in two patients due to renal impairment, in one patient due to peroneal nerve paresis, and in five patients due to persistent side effects that did not improve or disappear even after dose reduction (3–3 patients with liver function abnormalities and alopecia). Normalization of renal function was seen within 2–4 weeks after discontinuation of CsA treatment. AEs were mainly reversible (n = 78; 95.1%), but 1/92 (1.1%) patients died of opportunistic acute tuberculous pneumonia, 2/92 (2.2%) patients were on therapeutic anticoagulation for deep vein thrombosis, and 1/92 (1.1%) patients had continued to have epileptic seizures after CsA withdrawal.

Table 3.

The incidence and presentation of adverse events during CsA therapy.

Adverse events during CsA therapy
Patients with adverse events (n, %)	49 (53.3%)
Total number of adverse events occurred (n/patient)	82 (0.89/patient)
Infection	7 (7.6%)
Fever without infection	1 (1.1%)
Hyperlipidaemia	22 (23.9%)
Allergic reaction (mild symptoms, no intervention was needed)	1 (1.1%)
Gingival hyperplasia	2 (2.2%)
Renal dysfunction	2 (2.2%)
Neurological side effects	10 (10.9%)
Tremor	3 (3.3%)
Paresthesia	1 (1.1%)
Headache	2 (2.2%)
Seizure	1 (1.1%)
Peroneal nerve paresis	1 (1.1%)
Vertigo	2 (2.2%)
Gastrointestinal side effects	10 (10.9%)
Nausea	2 (2.2%)
Vomiting	2 (2.2%)
Abnormal hepatic function without jaundice	6 (6.5%)
Musculoskeletal side effects	7 (7.6%)
Myalgia	4 (4.4%)
Muscle cramps	2 (2.2%)
Arthralgia	1 (1.1%)
Dermatological side effects	9 (9.8%)
Alopecia	4 (4.4%)
Hypertrichosis	3 (3.3%)
Generalized edema	1 (1.1%)
Acne	1 (1.1%)
Cardiovascular side effects	11 (12.0%)
Hypertension, hypertensive crisis	8 (8.7%)
Heart palpitations	1 (1.1%)
Deep vein thrombosis	2 (2.2%)

CsA, cyclosporin; n, number of events.

The only predictor of adverse events during CsA was hypoalbuminaemia (<35 g/L; n = 59) at treatment initiation (Table 2; p = 0.03; OR: 0.36; 95% CI: 0.14, 0.91). The occurrence of AEs was not associated with the use of concomitant IMT (p = 0.92), biological or small-molecule agents (p = 0.50). The details of the predictive model are presented as Supplemental Material (Table S4).

Newly diagnosed malignancies were reported in 5.4% (5/92) of patients during follow-up (median 6.7 years after CsA initiation), which were mainly melanoma (n = 2) and non-melanoma skin cancer (n = 2), while one patient had papillary thyroid carcinoma.

Discussion

In this retrospective, single-center cohort, we found that 88.0% of severely active, steroid-refractory UC patients showed clinical response to IV CsA. After initial therapeutic response, 40.7% of patients achieved clinical remission, and its likelihood was increased by concomitant IMT use. Among CsA responders, 51.9% avoided colectomy during the median 14-year follow-up period. However, more than half of these patients eventually required treatment enhancement with biologics or small molecules to maintain therapeutic response or avoid colectomy in the long term.

One of the major advantages of CsA therapy is its rapid onset of action. Previous data on the short-term effectiveness of CsA treatment showed a clinical response rate of 62%–92% supporting our results.^{6,8,10,13,14,16,17,36–39} The rate of clinical remission with IV CsA was 53.8%–74% in earlier studies,^12,40 as compared to 23.9% observed in our cohort. A retrospective cohort of 85 patients found that the presence of Truelove-Witts criteria, UC symptoms lasting at least 6 weeks, and severe endoscopic lesions were associated with an increased risk of failure of IV CsA.⁴¹ Bamba et al.⁴² reported that the short-term effectiveness of CsA therapy was affected by the following three factors: more than 10,000 mg of prednisolon prior to CsA, presence of cytomegalovirus antigenemia, and disease duration more than 4 years. In contrast, in the present study, we did not find any factors predictive of IV CsA effectiveness. However, based on our results, patients who receive IMT in addition to CsA therapy are more likely to achieve clinical remission, and thereby avoid colectomy. Before the advent of biologics—and currently in settings where access is restricted by financial or national regulations—CsA is often used as a bridging therapy until immunomodulators reach full efficacy. This approach inevitably involves the combined use of immunosuppressive agents, which understandably raises concerns about the increased risk of infections or other AEs. However, neither previous studies nor our present cohort demonstrated an increased risk of adverse events associated with such combination therapy. In line with our findings, several cohorts even reported that patients receiving IMT in addition to CsA treatment required less surgical intervention than those who did not receive concomitant IMT.^{13,40,42–44} Nevertheless, we emphasize that careful patient selection remains critical with all immunosuppressive regimens, taking into account age, comorbidities, and overall clinical status.

In case of a severe UC flare-up, the aim of rescue therapy is to induce remission and stabilize the patient's condition in order to avoid colectomy. However, studies indicate that 27.8%–75% of patients experience relapse within 6 months to 1 year, especially if appropriate maintenance strategies are not implemented.^{12,36,38,40,45} In our cohort, 23.5% of patients relapsed within 6 months after CsA discontinuation, and 59.3% of patients eventually required additional treatment enhancement with biologics. Although the results are not directly comparable due to differences in follow-up periods, a study published by Eronen et al.³⁹ found that 31% of patients required advanced therapy after CsA rescue treatment. Similar to our results, which showed a colectomy-free survival rate of 74.7% at 1 year, 62.6% at 3 years, and 57.1% at 5 years, in previous cohorts the probability of colectomy avoidance after CsA therapy initiation was 64%–72%, 55%–58%, and 46%–58% at the same timepoints.^{13,38,43,44,46} A subanalysis of the 36 initial CsA responders included in the study by Cohen et al.¹³ revealed that 70% would be predicted to retain their colon at 5.5 years, while other smaller previous studies have shown that 45%–100% of CsA responders avoid colectomy at 4 months to 4.5 years after CsA withdrawal, as compared to 51.9% observed in our study over a median of 14 years.^8,12,47

Based on previous data, the most common side effects of CsA therapy are nephrotoxicity, hypertension, infections, gingival hyperplasia, hypertrichosis, and neurological complications, including headaches, paresthesias, and tremor. While the rate of CsA-related AEs seems to be high, nearly all AEs are dose-dependent and usually disappear as the treatment is discontinued or the dose is reduced.^18,48–50 In our cohort, the three most common AEs were hyperlipidaemia, hypertension, and infections, all with a frequency of less than 10%. The infectious complications resolved with conservative treatment in all but one patient, who died of acute TB pneumonia. The only predictor of AEs was hypoalbuminaemia at CsA treatment initiation. Hypoalbuminaemia is not only a poor prognostic marker in UC, but its presence may lead to an elevated free CsA concentration in the blood, potentially increasing the risk of toxicity.^51,52 The occurrence of AEs was not associated with the use of concomitant IMT, biological, or small-molecule agents. In addition, our results are in line with previously published data on postoperative complications in patients who received CsA treatment prior to colectomy.^12,53

In UC patients who do not respond to steroids, the introduction of salvage therapies such as CsA and IFX has provided alternatives to colectomy, which was previously the only remaining option. These two agents continue to represent the cornerstone of rescue therapy in ASUC. While their efficacy appears broadly comparable, questions remain regarding their true equivalence.^54,55 Several observational studies have compared CsA and IFX in terms of remission induction and colectomy avoidance, but results have been inconsistent.^54,56,57 Two randomized clinical trials directly compared CsA and IFX in steroid-refractory ASUC, reporting similar efficacy; however, a greater proportion of patients treated initially with CsA required subsequent advanced therapies compared to those receiving IFX. Despite persistent concerns regarding the safety profile of CsA, these trials found no significant differences in AEs or mortality rates between the two treatment arms.^58,59 Recently, a number of novel agents, such as vedolizumab, ustekinumab, and tofacitinib—have expanded the therapeutic landscape for UC; however, robust data on their use in ASUC are still lacking.⁵⁴ Given the limited therapeutic options for this patient population, comprehensive evaluation of the short and long-term effectiveness and safety of CsA remains particularly important, even as its role is increasingly questioned in the biological era.

We acknowledge some limitations in our study. The key limitation is its retrospective nature, which introduces confounding through inherent variability in assessments. Biochemical and endoscopic endpoints were not investigated. However, due to the relatively small number of patients and the retrospective nature of the study, we were unable to identify the minimum effective dosage and duration of concomitant IMT.

However, our study has several notable strengths. To the authors’ knowledge, this study has the longest follow-up time (a median of 14 years), which has given the opportunity to assess the long-term effectiveness and safety of CsA rescue therapy. Our cohort is also one of the largest to date, allowing not only to provide good quality data, but also to determine independent predictors of therapeutic response and colectomy.

Conclusion

Even in the era of advanced therapies, CsA may still be an effective therapeutic option to avoid acute colectomy and achieve remission in steroid-refractory, severely active UC. However, the risk of relapse after CsA discontinuation is substantial, necessitating close patient monitoring and a strategic approach to maintenance therapy. Our findings suggest that the effectiveness of CsA may be enhanced by the concomitant use of IMT in active, severe, steroid-refractory UC, without compromising safety. However, further studies are needed to optimize treatment protocols and improve long-term outcomes for this patient population.

Supplemental Material

sj-docx-1-tag-10.1177_17562848251361054 – Supplemental material for Short- and longevity outcome of cyclosporin rescue therapy in severe ulcerative colitis refractory to intravenous corticosteroid treatment

Supplemental material, sj-docx-1-tag-10.1177_17562848251361054 for Short- and longevity outcome of cyclosporin rescue therapy in severe ulcerative colitis refractory to intravenous corticosteroid treatment by Bernadett Farkas, Peter Bacsur, Anita Bálint, Emese Ivány, Mariann Rutka, Anna Fábián, Zsófia Bősze, Renáta Bor, Zoltán Szepes, Klaudia Farkas and Tamás Molnár in Therapeutic Advances in Gastroenterology

Supplemental Material

sj-docx-2-tag-10.1177_17562848251361054 – Supplemental material for Short- and longevity outcome of cyclosporin rescue therapy in severe ulcerative colitis refractory to intravenous corticosteroid treatment

Supplemental material, sj-docx-2-tag-10.1177_17562848251361054 for Short- and longevity outcome of cyclosporin rescue therapy in severe ulcerative colitis refractory to intravenous corticosteroid treatment by Bernadett Farkas, Peter Bacsur, Anita Bálint, Emese Ivány, Mariann Rutka, Anna Fábián, Zsófia Bősze, Renáta Bor, Zoltán Szepes, Klaudia Farkas and Tamás Molnár in Therapeutic Advances in Gastroenterology

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iDs

Bernadett Farkas

Peter Bacsur

Anna Fábián

Renáta Bor

Supplemental material

Supplemental material for this article is available online.

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