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Article

Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study

by
Anca Butuca
1,†,
Laurentiu Stoicescu
2,3,†,
Mirela Livia Popa
4,*,
Carmen Maximiliana Dobrea
1,*,
Adriana Muntean
5,
Claudiu Morgovan
1,
Corina Pienar
6,
Felicia Gabriela Gligor
1,
Steliana Ghibu
7,
Ioana Rada Popa Ilie
8 and
Adina Frum
1
1
Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania
2
Internal Medicine Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
3
Cardiology Department, Clinical Municipal Hospital, 400139 Cluj-Napoca, Romania
4
Clinic Medical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania
5
Clinical Institute of Urology and Renal Transplant Cluj-Napoca, 4-6 Clinicilor Str., 400006 Cluj-Napoca, Romania
6
Department of Pediatrics, 2nd Pediatrics Clinic, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
7
Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
8
Department of Endocrinology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 3-5 Louis Pasteur Street, 400349 Cluj-Napoca, Romania
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Clin. Med. 2025, 14(10), 3409; https://doi.org/10.3390/jcm14103409
Submission received: 5 March 2025 / Revised: 27 April 2025 / Accepted: 30 April 2025 / Published: 13 May 2025
(This article belongs to the Special Issue Clinical Practice and Personalized Medicine in Kidney Transplantation)
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Versions Notes

Abstract

:
Effective immunosuppressant pharmacotherapy is essential for successful organ transplantation. Background/Objectives: Generally, induction therapy includes basiliximab (BAS) or anti-thymocyte globulin (THY). However, other biological molecules have been used to accelerate firm immunosuppression. A reduced effectiveness of these induction agents increases the risk of graft rejection. This study aims to evaluate the ineffectiveness rate of biological molecules based on spontaneous reports uploaded to the EudraVigilance database. Methods: Specific topics related to the safety profiles of alemtuzumab, BAS, belatacept, and THY were analyzed. A total of 23 preferred terms describing drug resistance, drug ineffectiveness, and transplant rejection were used as the inclusion criteria. Descriptive and disproportionality analyses were performed. Results: Regarding the four molecules, 18,564 safety reports were communicated, with n = 5089 (27.4%) for THY and n = 3469 (18.7%) for BAS. Most adverse drug reactions (ADRs) for THY, BAS, and belatacept affected the adult male population. As expected, the majority of the ADRs were linked to infections, followed by general disorders. BAS presented higher probabilities of drug resistance and transplant rejection being reported among the four molecules. A higher probability of reporting drug ineffectiveness was noted for THY than for the other molecules. Conclusions: All the molecules showed small frequencies regarding resistance. As expected, transplant rejection was more frequently reported for all molecules (especially for BAS), accompanied by a notable variability in reporting frequencies. However, a causal relationship between the reported adverse reactions and drug efficacy cannot be established based on the present results. Further real-world evidence studies will enhance our understanding of the safety and efficacy of these drugs in transplant patients.

1. Introduction

Organ transplantation has achieved fulminant success over the last few decades due to a combined approach involving precision matching, surgical techniques, and effective immunosuppressant pharmacotherapy. In 2023, over 170,000 transplants were performed worldwide, 9.5% more than the previous year [1]. Kidney transplants accounted for the majority, making up more than half of the total [1], followed by liver transplants [2] and, to a much lesser extent, pancreas, intestine, and heart transplants [3,4,5].
The life expectancy of organ receivers depends on graft survival [6]. Donor–recipient compatibility is assessed through histocompatibility testing; however, even with high compatibility, lifelong immunosuppressive therapy is still required [7]. The human leukocyte antigen (HLA) system is involved in identifying “self” components and in triggering the immune response against “non-self” elements. It is highly polymorphic, and a good match to the donor increases the chances of organ acceptance, reducing allograft immunogenicity [8].
Regarding pharmacotherapy, international guidelines mention two major stages: induction and maintenance [9,10]. Initial regimen standard recommendations include calcineurin inhibitors, mycophenolate, steroids, and induction therapy using basiliximab (BAS) or anti-thymocyte globulin (THY) [9]. Belatacept [9], alemtuzumab [11], eculizumab [12], and rituximab [10] are other biological molecules that have been successfully used for the same purpose. This group contains molecules that have been newly introduced into the market. Several studies concerning both effectiveness [13,14] and cost-effectiveness have shown the benefits of antibodies for induction therapy [15,16] at an individual level and for health systems. Maintenance therapy is conducted with calcineurin inhibitors, mycophenolate, and steroids. The doses of steroids (prednisolone or methylprednisolone) and calcineurin inhibitors (tacrolimus—elective; cyclosporine—alternative) are reduced in later post-operative stages [9].
The medicinal products recommended for inducing immunosuppression have different mechanisms of action. BAS and rituximab are chimeric monoclonal antibodies. BAS acts on the surface of activated T-lymphocytes, blocking the CD25 antigen; specifically, the alpha chain of interleukin-2 receptors [17]. Rituximab binds to the CD20 antigen of B-cells and is used “off-label” for immunosuppression in transplant patients [18]. Its approved indications are CD20-positive B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, microscopic polyangiitis, granulomatosis with polyangiitis, and pemphigus vulgaris. Off-label uses include myasthenia gravis, multiple sclerosis, chronic steroid-refractory GVHD, Hodgkin lymphoma, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, Waldenstrom macroglobulinemia, and membranous nephropathy [19]. Alemtuzumab and eculizumab are humanized monoclonal antibodies. The former binds to CD52 and exerts a strong immunosuppressive effect by targeting multiple immune cell lines [20], while the latter binds to the complement protein C5 [12]. Belatacept is a protein that inhibits T-cell co-stimulation [21]. An intense immunosuppressive response is triggered by anti-thymocyte globulin, which consists of derived antibodies against T-cells, targeting both mature and immature forms [22] due to the antibodies’ ability to bind to a vast number of targets (e.g., CD1a, CD3/TR, CD4, CD6, CD7, CD8, CD16, CD25, CD30, CD32, CD 80, HLA class I heavy chains, and others) [23,24].
Two critical aspects are the main advantages of immunosuppression induction therapy; these aspects are the time of response and potency, aimed at accelerating firm immunosuppression. A reduced effectiveness of these induction agents increases the risk of graft rejection [15,16].
EudraVigilance (EV) is a platform launched by the European Medicines Agency in 2012, the main objective of which is to collect spontaneous reports of suspected adverse drug reactions (ADRs) [25,26,27,28]. In addition, disproportionality analysis is a validated method used in post-marketing drug safety surveillance.
This study evaluates the ineffectiveness rate of biological molecules used as immunosuppressant inductors based on real-world data comprising spontaneous reports uploaded to the EudraVigilance database.

2. Materials and Methods

2.1. Study Design

Based on individual case safety reports (ICSRs) uploaded to the EudraVigilance (EV) database up to 19 January 2025, available on https://www.adrreports.eu/, accessed on 22 January 2025, we conducted a pharmacovigilance study on ADRs reported for biological immunosuppressive induction agents used in transplant therapy (BIIAs). Individual case safety reports of four BIIAs (alemtuzumab, BAS, belatacept, and THY) were analyzed. Although many reports were uploaded to EV for eculizumab and rituximab, they were not included in the present study because immunosuppression induction in transplants is not their main indication, which may represent a confounding factor. Using data extracted on 21 January 2025, descriptive and disproportionality analyses were performed.

2.2. Descriptive Analysis

The first stage of this study comprises analyzing the distribution of ICSRs reported for BIIAs: alemtuzumab, BAS, belatacept, and THY. Further, a comparison of general characteristics data reported for all BIIAs was performed. Each ICSR contains four data categories: (i) patient age: 0–1 month, 2 months–2 years, 3–11 years, 12–17 years, 18–64 years, 65–85 years, over 85 years, or not specified (NS); (ii) sex (male, female, or NS); (iii) geographic origin of reports (European Economic Area (EEA), non-EEA, or NS); (iv) reporter category (healthcare professional (HP), non-HP, or NS). Subsequently, the frequency of reports with ADRs in each SOC, serious cases, and cases distributed based on SOCs were comparatively analyzed for the four BIIAs. Finally, a comparison between ADRs related to drug resistance, ineffectiveness, and transplant rejection was conducted. According to European Medicines Agency regulations, different preferred terms (PTs) can be used for reporting ADRs. In the present study, 2 PTs were used to evaluate drug resistance, 11 to evaluate drug ineffectiveness [29], and 11 to evaluate transplant rejection (Table 1).

2.3. Disproportionality Analysis

To establish the probability of ADR reporting, a disproportionality analysis was conducted. For each ADR group (drug resistance, drug ineffectiveness, and transplant rejection) reported for each BIIA, this probability was evaluated by comparing drugs used in related therapeutic areas or similar clinical contexts. Reporting odds ratios (RORs) and 95% confidence intervals (95% CI) must be calculated to identify similarities and differences in ADR reporting in EV [30,31]. The disproportionality analysis can be validated if a minimum of five cases is reported for each ADR and the lower limit of the 95% CI is above 1 [32,33,34]. The MedCalc application (retrieved from https://www.medcalc.org/calc/odds_ratio.php (Version 23.1.3) accessed on 28 January 2025) was used to calculate RORs and 95% CIs [35].

3. Results

3.1. Descriptive Analysis

3.1.1. ICSR Analysis

A total of 18,565 ICSRs were reported for the four BIIAs; 48.6% of the total (n = 9030) were related to alemtuzumab. The ICSRs reported for THY (n = 5089) and BAS (n = 3469)—specific biologicals used in post-transplant induction therapy—represented 27.4% and 18.7% of the total, respectively (Figure 1).
According to the data presented in Table 2, the majority of ICSRs related to THY (50.9%), BAS (58.4%), and alemtuzumab (56.7%) are registered in the 18–64-year age group. Additionally, the majority of reports on the use of THY (47.1%), BAS (55.1%), and belatacept (51.2%) were recorded for male patients. Except for alemtuzumab (38.1%), the origin of the reports was non-EEA (THY—67.6%; BAS—73.1%; belatacept—63.2%). Furthermore, HP was the main category of these reports.

3.1.2. ICSR Analysis

In this step, we calculated the frequency of SOCs per ICSR. The lowest value was calculated for belatacept (1.83) and the highest for BAS (2.56). Except for belatacept, all other BIIAs presented a similar ratio to BAS (Figure 2).
Figure 3 presents the ratio of cases with serious ADRs. Serious conditions were related to all drugs in a high percentage. Thus, over 90% of serious cases were observed for THY, BAS, and belatacept.
The highest relative SOC occurrence frequencies were recorded for the following categories (Table 3): (i) “General disorders and administration site conditions” (THY—11.5%; BAS—8.2%; alemtuzumab—11.9%; belatacept—8.8%); (ii) “Infections and infestations” (THY—15.4%; BAS—20.3%; alemtuzumab—11.1%; belatacept—23.1%); (iii) “Injury, poisoning, and procedural complications” (belatacept—15.0%); (iv) “Immune system disorders” (THY—10.7%; BAS—12.5%), and (v) “Nervous system disorders” (alemtuzumab—8.5%).

ADRs Related to Resistance, Ineffectiveness, and Transplant Rejection

According to Figure 4, the highest frequency of total ADRs related to drug resistance, transplant rejection, and drug ineffectiveness in the total cases was registered for BAS (31%), and the lowest frequency was observed for alemtuzumab (4%). Furthermore, alemtuzumab presented a lower proportion of resistance and rejection than the other BIIAs.

3.2. Disproportionality Analysis

3.2.1. Drug Resistance

Alemtuzumab has a lower probability of reporting resistance than BAS (ROR: 0.2; 95% CI: 0.1–0.3) and THY (ROR: 0.4; 95% CI: 0.2–0.8); conversely, BAS has a higher probability of reporting resistance (Figure 5). In addition, a higher probability of reporting was observed for THY than alemtuzumab. For belatacept, only three signals were documented in this category. As at least five cases are needed to compute the ROR, belatacept was excluded from this analysis (Figure 5).

3.2.2. Drug Ineffectiveness

Alemtuzumab and belatacept had a lower probability of reporting drug ineffectiveness than THY (alemtuzumab—ROR: 0.5; 95% CI: 0.4–0.6; belatacept—ROR: 0.4; 95% CI: 0.3–0.7) and BAS (alemtuzumab—ROR: 0.7; 95% CI: 0.6–0.8; belatacept—ROR: 0.6; 95% CI: 0.4–0.9). No difference was observed between belatacept and alemtuzumab (Figure 6).

3.2.3. Transplant Rejection

Regarding transplant rejection, alemtuzumab has a lower probability of being reported than all other BIIAs: BAS—ROR: 0.03; 95% CI: 0.03–0.04; THY—ROR: 0.13; 95% CI: 0.10–0.16; and belatacept—ROR: 0.08; 95% CI: 0.06–0.10. A lower probability of reporting rejection was observed for THY than for BAS (ROR: 0.27; 95% CI: 0.24–0.30) and belatacept (ROR: 0.60; 95% CI: 0.49–0.74) (Figure 7).

4. Discussion

Antibody induction therapy has increased substantially over the last 20 years [36]. Most reports uploaded to EV for this drug class involve adult subjects. In our study, specific data detailing the prevalence of ADRs for THY, BAS, and alemtuzumab were limited, but other research groups have reported ADRs associated with these drugs.
There were no major differences in gender in our analysis (Table 2), but the highest proportion of ADRs was recorded for men: THY, 47.10%; BAS, 55.1%; and belatacept, 51.2%. Our results agree with a multinational European study showing that fewer women than men undergo kidney transplants or receive induction therapy [37]. Alemtuzumab showed a different situation, presenting most reports (56.7%) for women. Another recent study reported 10 patients who developed fatal adverse effects during alemtuzumab treatment. Among these patients, one was male and nine were female, suggesting a higher incidence of adverse reactions in women in this small group [38].
Regarding the geographical origin of reports, our findings partially align with the results presented by Sheng et al., who identified the highest number of ADR reports coming from India [39], except alemtuzumab, for which the majority were filed from within the EEA.
Our findings show an over 90% frequency of serious ADRs for all BIIAs, except alemtuzumab (Figure 3). These results are supported by multiple studies. A clinical trial found that alemtuzumab therapy may be an alternative to glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection, with fewer infusion-related adverse events than THY. This research also suggests that alemtuzumab provides a safer profile for transplant recipients, reinforcing the idea that its lower rate of serious adverse reactions is clinically relevant [40].
The finding that the most frequently reported SOCs are “General disorders and administration site conditions”, “Infections and infestations”, and “Injury, poisoning, and procedural complications” is strongly supported by the literature. One investigation found that alemtuzumab induces prolonged lymphocyte depletion, leading to an increased risk of opportunistic infections, and proposed lower doses to reduce this risk [41]. This aligns with the observation that infections are a major concern in alemtuzumab-treated patients and are frequently categorized as “Infections and infestations”. A detailed examination reported infusion-related side effects following THY administration, which were associated with a significant increase in serum cytokine levels, particularly interleukin-6, indicating that THY can induce cytokine release syndrome [42]. All these findings confirm that THY triggers a strong immune response, leading to high-grade fevers, chills, and severe immune system overactivation. This aligns with the classification of adverse events under “Immune system disorders” for THY, reinforcing the hypothesis that a high frequency of adverse reactions for this drug is reported under this category. Aligning with our results categorized by SOC, a clinical trial reported that hypotension was the most common ADR for THY, occurring in 60% of cases, followed by hyperthermia (40%), agitation (30%), tachycardia (20%), hypertension (15%), tremors (10%), and nausea (5%) [43].
For alemtuzumab, similar results concerning infections, nervous disorders, general disorders, and blood disorders were reported by Zaza et al., indicating that alemtuzumab is associated with pyrexia, rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm [44]. A study that examined hematologic complications in lung transplant recipients found that patients receiving induction therapy with alemtuzumab or BAS developed bone marrow failure [45]. A research study on more than 1500 adverse drug event reports uploaded to FAERS—another well-established pharmacovigilance database—identified 295 preferred terms across 24 system organ classifications, with increased blood creatinine and pyrexia being the most frequently reported adverse events associated with BAS. This highlights the importance of closely monitoring kidney function and inflammatory markers in patients receiving this treatment [39]. At the same time, the most common adverse events associated with BAS include gastrointestinal issues, edema, fever, dyspnea, headache, acne, tremor, and insomnia. Additionally, anaphylactic reactions have been reported, suggesting that BAS use should be accompanied by careful patient monitoring [46,47].
In our study, the highest frequencies of ADRs related to drug resistance and transplant rejection in the total cases were registered for BAS, followed by belatacept and THY. A meta-analysis evaluated the efficacy of BAS compared with THY in renal transplantation and found no significant differences in the 1-year acute rejection rates between the two groups; the 1-year graft survival rates were similar. These findings suggest that BAS and THY have comparable efficacy in preventing acute rejection and promoting graft survival in renal transplant patients [48].
Multiple studies confirm our results showing that alemtuzumab has some of the lowest reported rates of resistance, inefficiency, and transplant rejection among total severe ADRs. A study assessing the long-term efficacy and safety of alemtuzumab in treating severe or glucocorticoid-resistant kidney transplant rejection found that over 60% of grafts were successfully preserved with alemtuzumab therapy, demonstrating its effectiveness in managing severe rejection episodes [49]. However, it also reported that graft survival was significantly poorer than that of a reference cohort, and there was a higher risk of serious infections and increased patient mortality associated with alemtuzumab treatment [49]. Another study reviewed kidney transplant rejection rates following a change in immunosuppression regimens due to the COVID-19 pandemic, observing that early follow-up results suggested a possibly higher rejection rate with BAS than with alemtuzumab. However, the authors noted that longer-term follow-up is necessary to draw stronger conclusions [50].
BAS has a higher probability of resistance than other medications, except for belatacept, which did not meet the inclusion criteria for this analysis (Figure 5). A clinical trial evaluating the efficacy of BAS induction therapy in kidney transplant recipients with a low immunological risk profile found that it did not provide a significant benefit in reducing acute rejection rates or improving graft survival within five years post-transplant compared with a non-induction approach [51].
Alemtuzumab and belatacept had a lower probability of reporting drug ineffectiveness than THY and BAS, but no difference was observed between belatacept and alemtuzumab. One study found that alemtuzumab was associated with a lower rate of treatment failure, indicating a lower probability of inefficacy [52]. We assessed other studies based on transplant registries and clinical trials to widen the perspective on the effectiveness of these drugs. We compared the safety signals observed by other clinicians with our results. A long-term (over 20 years) retrospective study on the effectiveness of induction immunosuppression based on the United Network for Organ Sharing Registry Data showed indisputable evidence of the benefits of induction therapy regarding short-term and long-term graft survival. It also captured various induction strategies and regimens recommended through the years. They concluded that depleting antibodies such as alemtuzumab are superior to non-deletional agents (BAS) in significantly reducing the risk of graft failure [53].
Lentile et al. found no significant differences in mortality, graft failure, or all-cause graft survival between participants receiving THY and those receiving BAS over 10 years. To obtain these findings, they employed a data integration approach utilizing a transplant registry database. This method facilitated the comprehensive collection and comparison of long-term outcome data for individuals enrolled in a clinical trial assessing the efficacy of THY versus BAS [54]. A study comparing serious unfavorable outcomes for kidney transplant patients—including death, sepsis, neoplasia, and healthcare assistance—up to a year after undergoing induction immunosuppression showed a favorable profile for THY compared with alemtuzumab and BAS [55]. Another multicenter cohort study on the efficacy and safety of BAS and THY showed similar profiles for both molecules [56].
Approximately 90% of the expert respondents who contributed to the European Consensus on the Management of Sensitized Kidney Transplant Recipients (2024) expressed strong agreement on the clinical value and effectiveness of utilizing alemtuzumab and THY in the treatment of this specific patient population. Their consensus highlights the growing recognition of these therapeutic approaches as essential strategies for improving transplant outcomes, optimizing patient management, and addressing the unique immunological challenges faced by sensitized kidney transplant recipients [57].
Regarding organ rejection, BAS is linked to the highest probability of reporting compared with all other medications (Figure 7). Several studies have shown a significantly higher incidence of acute rejection with BAS than with alemtuzumab [58,59].
According to transplant guidelines, THY is the first recommendation for patients at high risk of rejection, for whom THY seems to be more effective than BAS in preventing the incidence and severity of rejection. However, BAS is an alternative option in different categories: (i) patients unable to tolerate THY (e.g., allergies, leukopenia, thrombocytopenia, or chronic hypotension) [17,60,61]. In patients at low immunologic risk of acute rejection, either BAS or THY represents a reasonable strategy in induction therapy. Research also shows a lower rate of biopsy-proven acute rejection (BPAR) for THY [62] (tacrolimus, mycophenolate, and steroids) [51]. Another explanation for the high rejection rate reported for BAS could be its off-label use. Thus, the EMA and its manufacturer have warned healthcare specialists regarding the off-label use of BAS in cardiac transplants [63]. Moreover, the Summary of Product Characteristics also notes this warning, stating the risk of serious cardiac ADRs such as cardiac arrest and atrial flutter [64].
Furthermore, BAS is used off-label in the prophylaxis of acute rejection in liver or pulmonary transplantation [65,66]. Considering this off-label use, more reports of side effects are expected.
Compared with BAS, a lower probability of reporting transplant rejection was observed for BEL. Researchers have found that its use is associated with higher BPAR rates and grades than cyclosporine. Additionally, other serious adverse events have been observed, including post-transplant lymphoproliferative disorder, progressive multifocal leukoencephalopathy, and tuberculosis. This indicates that while belatacept offers immunosuppressive benefits, it may also introduce significant risks that need to be managed [67]. However, evidence also demonstrates that belatacept is a viable alternative to calcineurin-inhibitor-based immunosuppression [68], and another study suggests belatacept [69]. Moreover, our findings show a higher probability of reporting rejection for belatacept versus other BIIAs (except BAS). Belatacept is currently involved in a pilot, phase I/II clinical trial (ATTAIN) to desensitize kidney transplant candidates with calculated Panel Reactive Antibody (cPRA) values ≥ 99.9%, together with daratumumab, a CD38 monoclonal antibody used in multiple myeloma. Its favorable outcomes have encouraged the continuation of the trial [70].

Limitations of This Study

Our study is based on data obtained from the EV online platform, and its limitations are common to this kind of approach. An inherent limitation stems from the nature of the spontaneous reporting system, which is prone to under-reporting. This under-reporting can vary based on the specific drug, event type, and severity, ultimately impacting the results. Further skewed reports and lack of data such as age and gender in many ICSRs may also affect our research. Evaluating results in the absence of a clear definition of the population at risk can also lead to an incomplete or distorted process, thus limiting the ability to estimate the true incidence and nature of the observed events. At the same time, our study did not include information on other commonly used drugs; therefore, we could not determine whether the patients used other drugs at the same time. We did not assess a causal relationship between suspected drugs and spontaneously reported adverse reactions, but unlike data obtained from routine clinical trials, all spontaneous reports are suspected cases of adverse reactions. The ability to estimate the actual incidence of adverse events can be affected by biased reporting, often influenced by the phenomenon of under-reporting. Various factors may influence and trigger a failure to report an adverse event during treatment, including lack of awareness of pharmacovigilance, inadequate risk perception, mistrust, guilt, or ignorance. The EMA has observed regional and national differences regarding the variability of spontaneously reported data in EV, which can be attributed to variations in the existence and effectiveness of promotion campaigns [71]. Moreover, certain information regarding clinical characteristics (e.g., BPAR) may be inconsistent or even absent from these reports [72]. Since the EMA acknowledges these limitations, a direct causal correlation cannot be conclusively established based solely on these reports. Moreover, EV explicitly advises against such an approach [73]. Despite all these limitations, our study provides a comprehensive post-marketing analysis of drug safety. The data used were collected from the real world and a large and diverse population through spontaneous reporting systems. The large sample size not only enhances the generalizability of our findings but also helps mitigate potential errors, providing a solid basis for safety assessments. Disproportionality analysis from spontaneous reporting platforms, despite its inherent limitations, is now a validated method used in post-marketing drug safety surveillance.

5. Conclusions

Immunosuppressive pharmacotherapy is used both for induction and continuously after transplantation. To ensure accelerated, intense immunosuppression, new biomedicines have been authorized and prescribed for induction, including BAS, THY, alemtuzumab, and belatacept. This study aimed to investigate their ineffectiveness rates, as reported in an international pharmacovigilance database, EV. Ineffectiveness can be reported under various preferred terms accepted by international regulatory authorities.
The number of reported adverse reactions related to ineffectiveness and resistance was low across all four molecules. Compared with all BIIAs, BAS showed high probabilities of drug resistance and transplant rejection being reported. Pharmacovigilance database studies complement clinical trial data and improve the assessment of drug safety profiles. Post-market surveillance data across diverse patient populations and clinical settings offer valuable insights into long-term safety, rare adverse events, and treatment patterns. Thus, pharmacovigilance studies assist clinicians in making decisions based on evidence. Due to the complexity of transplantation procedures and the inherent constraints of observational data, a causal relationship between reported adverse reactions and drug efficacy cannot be implied, and a ranking of these therapeutic agents cannot be established. Further real-world evidence studies will enhance our understanding of the safety and efficacy of these drugs in transplant patients.

Author Contributions

Conceptualization, A.B., L.S., C.M.D., M.L.P. and A.M.; methodology, A.B., L.S., C.M.D., C.M. and A.F.; software, A.B., L.S., M.L.P., C.M.D. and C.P.; validation, M.L.P., C.M.D., A.M. and I.R.P.I.; formal analysis, A.B., L.S., C.M. and S.G.; investigation, A.B., L.S., C.M.D., M.L.P. and A.M.; resources, A.B., L.S. and A.F.; writing—original draft preparation A.B., L.S., C.M.D., M.L.P. and A.M.; writing—review and editing, C.M.D., M.L.P., A.M., S.G., I.R.P.I., F.G.G. and A.F.; visualization, A.B., L.S., C.M.D., M.L.P., A.M., C.M., C.P., S.G., F.G.G. and A.F.; supervision, M.L.P., C.M.D. and C.P.; project administration, A.B., L.S., C.M.D., A.M. and A.F. All authors have read and agreed to the published version of the manuscript.

Funding

This project was financed by Lucian Blaga University of Sibiu through research grant LBUS-IRG-2023 No. 3536/24.07.2023.

Institutional Review Board Statement

Ethical approval is not required for this study in accordance with local or national guidelines since this is a retrospective study conducted on cases of common clinical practice.

Informed Consent Statement

The requirement for written informed consent was waived due to the retrospective nature of the study.

Data Availability Statement

The data are contained in the article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Global Observatory on Donation and Transplantation. Available online: https://www.transplant-observatory.org/ (accessed on 19 January 2025).
  2. Scarpa, J. Improving Liver Transplant Outcomes with Transplant-Omics and Network Biology. Curr. Opin. Organ. Transplant. 2023, 28, 412–418. [Google Scholar] [CrossRef]
  3. Niederhaus, S.V. Pancreas Transplant Alone. Curr. Opin. Organ. Transplant. 2015, 20, 115–120. [Google Scholar] [CrossRef]
  4. Garcia, J.; Selvaggi, G.; Tekin, A.; Vianna, R. Intestinal Transplantation. Curr. Opin. Organ. Transplant. 2021, 26, 229–233. [Google Scholar] [CrossRef]
  5. Siddiqi, H.K.; Trahanas, J.; Xu, M.; Wells, Q.; Farber-Eger, E.; Pasrija, C.; Amancherla, K.; Debose-Scarlett, A.; Brinkley, D.M.; Lindenfeld, J.A.; et al. Outcomes of Heart Transplant Donation After Circulatory Death. J. Am. Coll. Cardiol. 2023, 82, 1512–1520. [Google Scholar] [CrossRef] [PubMed]
  6. Gruttadauria, M.; Dunn, C.; Lin, J.; Kaminetsky, J.R.; Applebaum, K.; Portal, D.; Mohammed, O.; Rocca, J.; Greenstein, S. Patients’ Expectations for Longevity of Kidney Transplant. Prog. Transplant. 2018, 29, 48–53. [Google Scholar] [CrossRef] [PubMed]
  7. Wood-Trageser, M.A.; Xu, Q.; Zeevi, A.; Randhawa, P.; Lesniak, D.; Demetris, A.J. Precision Transplant Pathology. Curr. Opin. Organ. Transplant. 2020, 25, 412–419. [Google Scholar] [CrossRef] [PubMed]
  8. Alelign, T.; Ahmed, M.M.; Bobosha, K.; Tadesse, Y.; Howe, R.; Petros, B. Kidney Transplantation: The Challenge of Human Leukocyte Antigen and Its Therapeutic Strategies. J. Immunol. Res. 2018, 2018, 5986740. [Google Scholar] [CrossRef]
  9. EAU Guidelines on Renal Transplantation; European Association of Urology: Arnhem, The Netherlands, 2024.
  10. Bauer, A.C.; Franco, R.F.; Manfro, R.C. Immunosuppression in Kidney Transplantation: State of the Art and Current Protocols. Curr. Pharm. Des. 2020, 26, 3440–3450. [Google Scholar] [CrossRef]
  11. Brook, M.O.; Hennessy, C.; Hester, J.; Hammad, S.; Alzhrani, A.; Rombach, I.; Dutton, S.; Lombardi, G.; Wood, K.J.; Friend, P.; et al. Late Treatment with Autologous Expanded Regulatory T-Cell Therapy After Alemtuzumab Induction Is Safe and Facilitates Immunosuppression Minimization in Living Donor Renal Transplantation. Transplantation 2024, 108, 2278–2286. [Google Scholar] [CrossRef]
  12. Barnett, A.N.R.; Asgari, E.; Chowdhury, P.; Sacks, S.H.; Dorling, A.; Mamode, N. The Use of Eculizumab in Renal Transplantation. Clin. Transplant. 2013, 27, E216–E229. [Google Scholar] [CrossRef]
  13. Masset, C.; Kerleau, C.; Blancho, G.; Hourmant, M.; Walencik, A.; Ville, S.; Kervella, D.; Cantarovich, D.; Houzet, A.; Giral, M.; et al. Very Low Dose Anti-Thymocyte Globulins Versus Basiliximab in Non-Immunized Kidney Transplant Recipients. Transplant. Int. 2023, 36, 10816. [Google Scholar] [CrossRef] [PubMed]
  14. Martinez-Mier, G.; Moreno-Ley, P.I.; Budar-Fernández, L.F.; Méndez-López, M.T.; Allende-Castellanos, C.A.; Jiménez-López, L.A.; Barrera-Amoros, D.A.; Reyes-Ruiz, J.M. Low-Dose Thymoglobulin versus Basiliximab Induction Therapy in Low-Risk Living Related Kidney Transplant Recipients: Three-Year Follow-Up Study. Arch. Med. Res. 2024, 55, 103047. [Google Scholar] [CrossRef] [PubMed]
  15. Gharibi, Z.; Ayvaci, M.U.S.; Hahsler, M.; Giacoma, T.; Gaston, R.S.; Tanriover, B. Cost-Effectiveness of Antibody-Based Induction Therapy in Deceased Donor Kidney Transplantation in the United States. Transplantation 2017, 101, 1234–1241. [Google Scholar] [CrossRef]
  16. Kamal, J.; Doyle, A. Immunosuppression and Kidney Transplantation. Handb. Exp. Pharmacol. 2021, 272, 165–179. [Google Scholar] [CrossRef]
  17. Ponticelli, C. Basiliximab: Efficacy and Safety Evaluation in Kidney Transplantation. Expert. Opin. Drug Saf. 2014, 13, 373–381. [Google Scholar] [CrossRef]
  18. Chauhan, K.; Mehta, A.A. Rituximab in Kidney Disease and Transplant. Animal Model. Exp. Med. 2019, 2, 76–82. [Google Scholar] [CrossRef] [PubMed]
  19. Saber, M.; Groves, R.W. Rituximab. Handbook of Systemic Drug Treatment in Dermatology, 2nd ed.; CRC Press: Boca Raton, FL, USA, 2024; pp. 233–239. [Google Scholar] [CrossRef]
  20. Guilcher, G.M.T.; Shah, R.; Shenoy, S. Principles of Alemtuzumab Immunoablation in Hematopoietic Cell Transplantation for Non-Malignant Diseases in Children: A Review. Pediatr. Transplant. 2018, 22, e13142. [Google Scholar] [CrossRef]
  21. Thomas, B.; Weir, M.R. Immunosuppression. In Nephrology Secrets, 4th ed.; Elsevier: Amsterdam, The Netherlands, 2019; pp. 405–409. [Google Scholar] [CrossRef]
  22. Mashima, K.; Oh, I.; Fujiwara, K.; Izawa, J.; Takayama, N.; Nakano, H.; Kawasaki, Y.; Minakata, D.; Yamasaki, R.; Morita, K.; et al. Comparison of Alemtuzumab, Anti-Thymocyte Globulin, and Post-Transplant Cyclophosphamide for Graft-versus-Host Disease and Graft-versus-Leukemia in Murine Models. PLoS ONE 2021, 16, e0245232. [Google Scholar] [CrossRef]
  23. Acharya, S.; Lama, S.; Kanigicherla, D.A. Anti-Thymocyte Globulin for Treatment of T-Cell-Mediated Allograft Rejection. World J. Transplant. 2023, 13, 299–308. [Google Scholar] [CrossRef]
  24. Mueller, T.F. Mechanisms of Action of Thymoglobulin. Transplantation 2007, 84, S5–S10. [Google Scholar] [CrossRef]
  25. Dubrall, D.; Leitzen, S.; Toni, I.; Stingl, J.; Schulz, M.; Schmid, M.; Neubert, A.; Sachs, B. Descriptive Analysis of Adverse Drug Reaction Reports in Children and Adolescents from Germany: Frequently Reported Reactions and Suspected Drugs. BMC Pharmacol. Toxicol. 2021, 22, 56. [Google Scholar] [CrossRef] [PubMed]
  26. Pozsgai, K.; Szűcs, G.; Kőnig-Péter, A.; Balázs, O.; Vajda, P.; Botz, L.; Vida, R.G. Analysis of Pharmacovigilance Databases for Spontaneous Reports of Adverse Drug Reactions Related to Substandard and Falsified Medical Products: A Descriptive Study. Front. Pharmacol. 2022, 13, 964399. [Google Scholar] [CrossRef] [PubMed]
  27. European Database of Suspected Adverse Drug Reaction Reports—Search. Available online: https://www.adrreports.eu/en/search_subst.html# (accessed on 25 March 2025).
  28. Crisafulli, S.; Khan, Z.; Karatas, Y.; Tuccori, M.; Trifirò, G. An Overview of Methodological Flaws of Real-World Studies Investigating Drug Safety in the Post-Marketing Setting. Expert. Opin. Drug Saf. 2023, 22, 373–380. [Google Scholar] [CrossRef]
  29. Vintila, B.I.; Arseniu, A.M.; Butuca, A.; Sava, M.; Bîrluțiu, V.; Rus, L.L.; Axente, D.D.; Morgovan, C.; Gligor, F.G. Adverse Drug Reactions Relevant to Drug Resistance and Ineffectiveness Associated with Meropenem, Linezolid, and Colistin: An Analysis Based on Spontaneous Reports from the European Pharmacovigilance Database. Antibiotics 2023, 12, 918. [Google Scholar] [CrossRef]
  30. Morgovan, C.; Dobrea, C.M.; Chis, A.A.; Juncan, A.M.; Arseniu, A.M.; Rus, L.L.; Gligor, F.G.; Ardelean, S.A.; Stoicescu, L.; Ghibu, S.; et al. A Descriptive Analysis of Direct Oral Anticoagulant Drugs Dosing Errors Based on Spontaneous Reports from the EudraVigilance Database. Pharmaceuticals 2023, 16, 455. [Google Scholar] [CrossRef]
  31. Grundmark, B.; Holmberg, L.; Garmo, H.; Zethelius, B. Reducing the Noise in Signal Detection of Adverse Drug Reactions by Standardizing the Background: A Pilot Study on Analyses of Proportional Reporting Ratios-by-Therapeutic Area. Eur. J. Clin. Pharmacol. 2014, 70, 627–635. [Google Scholar] [CrossRef]
  32. Pop, G.; Farcaș, A.; Butucă, A.; Morgovan, C.; Arseniu, A.M.; Pumnea, M.; Teodoru, M.; Gligor, F.G. Post-Marketing Surveillance of Statins—A Descriptive Analysis of Psychiatric Adverse Reactions in EudraVigilance. Pharmaceuticals 2022, 15, 1536. [Google Scholar] [CrossRef]
  33. Screening for Adverse Reactions in EudraVigilance. European Medicine Agency. Available online: https://www.ema.europa.eu/en/documents/other/screening-adverse-reactions-eudravigilance_en.pdf (accessed on 27 August 2024).
  34. Morgovan, C.; Dobrea, C.M.; Butuca, A.; Arseniu, A.M.; Frum, A.; Rus, L.L.; Chis, A.A.; Juncan, A.M.; Gligor, F.G.; Georgescu, C.; et al. Safety Profile of the Trastuzumab-Based ADCs: Analysis of Real-World Data Registered in EudraVigilance. Biomedicines 2024, 12, 953. [Google Scholar] [CrossRef] [PubMed]
  35. MedCalc Software Ltd. Odds Ratio Calculator. Version 23.1.3. Available online: https://www.medcalc.org/manual/odds-ratio.php (accessed on 22 January 2025).
  36. Ciancio, G.; Burke, G.W.; Miller, J. Induction Therapy in Renal Transplantation: An Overview of Current Developments. Drugs 2007, 67, 2667–2680. [Google Scholar] [CrossRef]
  37. Antlanger, M.; Noordzij, M.; van de Luijtgaarden, M.; Carrero, J.J.; Palsson, R.; Finne, P.; Hemmelder, M.H.; Aresté-Fosalba, N.; Reisæter, A.V.; Cases, A.; et al. Sex Differences in Kidney Replacement Therapy Initiation and Maintenance. Clin. J. Am. Soc. Nephrol. 2019, 14, 1616–1625. [Google Scholar] [CrossRef]
  38. Holmøy, T.; Fevang, B.; Olsen, D.B.; Spigset, O.; Bø, L. Adverse Events with Fatal Outcome Associated with Alemtuzumab Treatment in Multiple Sclerosis. BMC Res. Notes 2019, 12, 497. [Google Scholar] [CrossRef] [PubMed]
  39. Chen, S.; Ma, X.; Zhang, J. Safety Assessment of Basiliximab Using Real-World Adverse Event Data from the FDA Adverse Event Reporting System Database: A Retrospective Observational Study. Medicine 2024, 103, e39537. [Google Scholar] [CrossRef]
  40. van der Zwan, M.; Clahsen-Van Groningen, M.C.; van den Hoogen, M.W.; Kho, M.M.; Roodnat, J.I.; Mauff, K.A.L.; Roelen, D.L.; van Agteren, M.; Baan, C.C.; Hesselink, D.A. Comparison of alemtuzumab and anti-thymocyte globulin treatment for acute kidney allograft rejection. Transplantation 2020, 104, S367. [Google Scholar] [CrossRef]
  41. Guthoff, M.; Berger, K.; Althaus, K.; Mühlbacher, T.; Bakchoul, T.; Steurer, W.; Nadalin, S.; Königsrainer, A.; Heyne, N. Low-Dose Alemtuzumab Induction in a Tailored Immunosuppression Protocol for Sensitized Kidney Transplant Recipients. BMC Nephrol. 2020, 21, 178. [Google Scholar] [CrossRef]
  42. Khanolkar, R.A.; Dookie, S.; Li, N.; Khan, F.; Storek, J. Proinflammatory Cytokine Release and Infusional Side-Effects after Anti-Thymocyte Globulin Serotherapy for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. Blood 2023, 142, 6782. [Google Scholar] [CrossRef]
  43. Mendes, B.; Figueiredo, C.; Cabral, M.; Borba, A.; Mineiro, A.; Cardoso, J.; Calvinho, P.; Semedo, L.; Fragata, J. Basiliximab vs. Antithymocyte Globulin as Initial Induction Therapy for Lung Transplantation: A National Two Years Review. Transplantology 2022, 3, 267–274. [Google Scholar] [CrossRef]
  44. Zaza, G.; Tomei, P.; Granata, S.; Boschiero, L.; Lupo, A. Monoclonal Antibody Therapy and Renal Transplantation: Focus on Adverse Effects. Toxins 2014, 6, 869–891. [Google Scholar] [CrossRef] [PubMed]
  45. Hannan, S.J.; Iasella, C.J.; Sutton, R.M.; Popescu, I.D.; Koshy, R.; Burke, R.; Chen, X.; Zhang, Y.; Pilewski, J.M.; Hage, C.A.; et al. Lung Transplant Recipients with Telomere-Mediated Pulmonary Fibrosis Have Increased Risk for Hematologic Complications. Am. J. Transplant. 2023, 23, 1590–1602. [Google Scholar] [CrossRef]
  46. Sasaki, H.; Chikaraishi, T.; Furuhata, S.; Tsutsumi, H.; Miyano, S.; Nakano, T.; Sato, Y.; Kimura, K.; Takahashi, T. Anaphylactic Reaction After Initial Exposure of Basiliximab: Case Reports. Transplant. Proc. 2007, 39, 3457–3459. [Google Scholar] [CrossRef]
  47. Guillermo, F.; Patricia, L.; Vanina, B.; Rodolfo, M. Anaphylactic Reaction After Initial Exposure to Basiliximab. Res. Rev. J. Med. Health Sci. 2018, 7, 3457–3459. [Google Scholar]
  48. Wang, K.; Xu, X.; Fan, M. Induction Therapy of Basiliximab versus Antithymocyte Globulin in Renal Allograft: A Systematic Review and Meta-Analysis. Clin. Exp. Nephrol. 2018, 22, 684–693. [Google Scholar] [CrossRef] [PubMed]
  49. van Vugt, L.K.; van der Zwan, M.; Clahsen-van Groningen, M.C.; van Agteren, M.; Hullegie-Peelen, D.M.; De Winter, B.C.M.; Reinders, M.E.J.; Miranda Afonso, P.; Hesselink, D.A. A Decade of Experience with Alemtuzumab Therapy for Severe or Glucocorticoid-Resistant Kidney Transplant Rejection. Transplant. Int. 2023, 36, 11834. [Google Scholar] [CrossRef]
  50. Rai, J.; Sinha, S. EP-506 Kidney Transplant Rejection Rate Comparing Alemtuzumab versus Basiliximab during Covid Pandemic against Pre-Covid Period. Br. J. Surg. 2022, 109, znac245.123. [Google Scholar] [CrossRef]
  51. Lacave, F.; de Terwangne, C.; Darius, T.; Buemi, A.; Mourad, M.; France, Y.; Cardoso Coelho, J.; Fernandes, G.; Goffin, E.; Devresse, A.; et al. Basiliximab vs. No Induction Therapy in Kidney Transplant Recipients with a Low Immunological Risk Profile Receiving Tacrolimus/Mycophenolate/Steroids Maintenance Immunosuppression. J. Clin. Med. 2024, 13, 6151. [Google Scholar] [CrossRef] [PubMed]
  52. La Hoz, R.M.; Baddley, J.W. Infectious Complications of Immune Modulatory Agents. Curr. Infect. Dis. Rep. 2013, 15, 465–471. [Google Scholar] [CrossRef] [PubMed]
  53. Cai, J.; Terasaki, P.I. Induction Immunosuppression Improves Long-Term Graft and Patient Outcome in Organ Transplantation: An Analysis of United Network for Organ Sharing Registry Data. Transplantation 2010, 90, 1511–1515. [Google Scholar] [CrossRef]
  54. Lentine, K.L.; Schnitzler, M.A.; Xiao, H.; Brennan, D.C. Long-Term Safety and Efficacy of Antithymocyte Globulin Induction: Use of Integrated National Registry Data to Achieve Ten-Year Follow-up of 10-10 Study Participants. Trials 2015, 16, 365. [Google Scholar] [CrossRef]
  55. Koyawala, N.; Silber, J.H.; Rosenbaum, P.R.; Wang, W.; Hill, A.S.; Reiter, J.G.; Niknam, B.A.; Even-Shoshan, O.; Bloom, R.D.; Sawinski, D.; et al. Comparing Outcomes between Antibody Induction Therapies in Kidney Transplantation. J. Am. Soc. Nephrol. 2017, 28, 2188–2200. [Google Scholar] [CrossRef]
  56. Hong, S.Y.; Kim, Y.S.; Jin, K.; Han, S.; Yang, C.W.; Chung, B.H.; Park, W.Y. The Comparative Efficacy and Safety of Basiliximab and Antithymocyte Globulin in Deceased Donor Kidney Transplantation: A Multicenter Cohort Study; The Korean Society of Nephrology: Seoul, Republic of Korea, 2023; Volume 42, p. 138. [Google Scholar]
  57. Furian, L.; Bestard, O.; Budde, K.; Cozzi, E.; Diekmann, F.; Mamode, N.; Naesens, M.; Pengel, L.H.M.; Schwartz Sorensen, S.; Vistoli, F.; et al. European Consensus on the Management of Sensitized Kidney Transplant Recipients: A Delphi Study. Transplant. Int. 2024, 37, 12475. [Google Scholar] [CrossRef]
  58. Asderakis, A.; Sabah, T.K.; Watkins, W.J.; Khalid, U.; Szabo, L.; Stephens, M.R.; Griffin, S.; Chavez, R. Thymoglobulin Versus Alemtuzumab Versus Basiliximab Kidney Transplantation from Donors After Circulatory Death. Kidney Int. Rep. 2022, 7, 732–740. [Google Scholar] [CrossRef]
  59. Furukawa, M.; Chan, E.G.; Ryan, J.P.; Hyzny, E.J.; Sacha, L.M.; Coster, J.N.; Pilewski, J.M.; Lendermon, E.A.; Kilaru, S.D.; McDyer, J.F.; et al. Induction Strategies in Lung Transplantation: Alemtuzumab vs. Basiliximab a Single-Center Experience. Front. Immunol. 2022, 13, 864545. [Google Scholar] [CrossRef] [PubMed]
  60. Brennan, D.C.; Daller, J.A.; Lake, K.D.; Cibrik, D.; Del Castillo, D. Rabbit Antithymocyte Globulin versus Basiliximab in Renal Transplantation. N. Engl. J. Med. 2006, 355, 1967–1977. [Google Scholar] [CrossRef]
  61. Kim, J.M.; Jang, H.R.; Kwon, C.H.D.; Huh, W.S.; Kim, G.S.; Kim, S.J.; Joh, J.W.; Oh, H.Y. Rabbit Antithymocyte Globulin Compared with Basiliximab in Kidney Transplantation: A Single-Center Study. Transplant. Proc. 2012, 44, 167–170. [Google Scholar] [CrossRef] [PubMed]
  62. Hardinger, K.L.; Brennan, D.C.; Schnitzler, M.A. Rabbit Antithymocyte Globulin Is More Beneficial in Standard Kidney than in Extended Donor Recipients. Transplantation 2009, 87, 1372–1376. [Google Scholar] [CrossRef]
  63. Basiliximab: Off-Label Use Warnings for Cardiac Transplantation. React. Wkly. 2014, 1520, 1. [CrossRef]
  64. CHMP—Simulect: Annex I Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/product-information/simulect-epar-product-information_en.pdf (accessed on 23 March 2025).
  65. Spada, M.; Petz, W.; Bertani, A.; Riva, S.; Sonzogni, A.; Giovannelli, M.; Torri, E.; Torre, G.; Colledan, M.; Gridelli, B. Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients under Tacrolimus Immunosuppression. Am. J. Transplant. 2006, 6, 1913–1921. [Google Scholar] [CrossRef]
  66. Swarup, R.; Allenspach, L.L.; Nemeh, H.W.; Stagner, L.D.; Betensley, A.D. Timing of Basiliximab Induction and Development of Acute Rejection in Lung Transplant Patients. J. Heart Lung Transplant. 2011, 30, 1228–1235. [Google Scholar] [CrossRef] [PubMed]
  67. Archdeacon, P.; Dixon, C.; Belen, O.; Albrecht, R.; Meyer, J. Summary of the US FDA Approval of Belatacept. Am. J. Transplant. 2012, 12, 554–562. [Google Scholar] [CrossRef]
  68. Holdaas, H.; Mjøen, G.; Jardine, A.G. Belatacept: Where the BENEFITS Outweigh the Risk. Am. J. Kidney Dis. 2017, 69, 561–563. [Google Scholar] [CrossRef]
  69. Abramowicz, D.; Oberbauer, R.; Heemann, U.; Viklicky, O.; Peruzzi, L.; Mariat, C.; Crespo, M.; Budde, K.; Oniscu, G.C. Recent Advances in Kidney Transplantation: A Viewpoint from the Descartes Advisory Board. Nephrol. Dial. Transplant. 2018, 33, 1699–1707. [Google Scholar] [CrossRef]
  70. Vincenti, F.; Chandran, S.; Raja, R.; Mason, K.; Mall, S.; Maruthamuthu, S.; Martin, T.; Breeden, C.; Silva, J. Impact of Daratumumab and Belatacept on HlA Antibodies in Kidney Transplant Candidates with 100% CPRA: Early Results of ATTAIN (ITN090ST). Nephrol. Dial. Transplant. 2023, 38, gfad063a_6402. [Google Scholar] [CrossRef]
  71. Pinheiro, L.; Miguel, E.; Maciá, Á.; Stroe, R. Spontaneous Adverse Drug Reactions Subgroup Report César Hernandez García, ES (Subgroup Lead). Available online: https://www.ema.europa.eu/en/documents/report/spontaneous-adverse-drug-reactions-subgroup-report_en.pdf (accessed on 23 March 2025).
  72. Calapai, F.; Ammendolia, I.; Cardia, L.; Currò, M.; Calapai, G.; Esposito, E.; Mannucci, C. Pharmacovigilance of Risankizumab in the Treatment of Psoriasis and Arthritic Psoriasis: Real-World Data from EudraVigilance Database. Pharmaceutics 2023, 15, 1933. [Google Scholar] [CrossRef]
  73. European Database of Suspected Adverse Drug Reaction Reports—Disclaimer. Available online: https://www.adrreports.eu/en/disclaimer.html (accessed on 22 March 2025).
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Figure 1. Distribution of ICSRs reported for biological immunosuppressive induction agents used in transplant therapy. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
Figure 1. Distribution of ICSRs reported for biological immunosuppressive induction agents used in transplant therapy. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
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Figure 2. The average number of SOCs reported for each ICSR. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
Figure 2. The average number of SOCs reported for each ICSR. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
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Figure 3. Comparison between cases with serious ADRs reported for BIIAs. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
Figure 3. Comparison between cases with serious ADRs reported for BIIAs. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
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Figure 4. Frequencies of drug resistance, transplant rejection, and drug ineffectiveness in total cases. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
Figure 4. Frequencies of drug resistance, transplant rejection, and drug ineffectiveness in total cases. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
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Figure 5. Disproportionality analysis of drug resistance. ALE—alemtuzumab; BAS—basiliximab; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). * p < 0.05; ** p ≤ 0.01; **** p ≤ 0.0001.
Figure 5. Disproportionality analysis of drug resistance. ALE—alemtuzumab; BAS—basiliximab; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). * p < 0.05; ** p ≤ 0.01; **** p ≤ 0.0001.
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Figure 6. Disproportionality analysis of drug inefficacy. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). * p < 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.
Figure 6. Disproportionality analysis of drug inefficacy. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). * p < 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001.
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Figure 7. Disproportionality analysis of transplant rejection. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). **** p ≤ 0.0001.
Figure 7. Disproportionality analysis of transplant rejection. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit). **** p ≤ 0.0001.
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Table 1. PTs used for reported ADRs related to drug resistance, drug ineffectiveness, or transplant rejection.
Table 1. PTs used for reported ADRs related to drug resistance, drug ineffectiveness, or transplant rejection.
ADRPT
Drug resistanceDrug resistance
Multiple-drug resistance
Drug ineffectivenessDrug ineffective
Drug effect less than expected
Therapeutic product effect decreased
Therapeutic product effect incomplete
Therapeutic product ineffective
Therapeutic response decreased
Therapeutic response shortened
Therapy non-responder
Therapy partial responder
Treatment failure
Decreased activity
Transplant rejectionBone marrow transplant rejection
Heart transplant rejection
Intestine transplant rejection
Kidney transplant rejection
Liver transplant rejection
Lung transplant rejection
Multiple organ transplant rejection
Pancreas transplant rejection
Renal and pancreas transplant rejection
Skin graft rejection
Transplant rejection
Table 2. Comparison between the general characteristics of reports submitted to the EudraVigilance database. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit); HP—healthcare professional; NS—not specified.
Table 2. Comparison between the general characteristics of reports submitted to the EudraVigilance database. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit); HP—healthcare professional; NS—not specified.
THYBASALEBEL
n%n%n%n%
Age
NS108521.3%76021.9%285831.7%40441.4%
0–1 Month70.1%10.0%130.1%20.2%
2 Months–2 Years2254.4%812.3%1561.7%00.0%
3–11 Years4949.7%1704.9%2092.3%10.1%
12–17 Years3356.6%1424.1%1561.7%30.3%
18–64 Years259050.9%202758.4%512256.7%37538.4%
65–85 Years3536.9%2888.3%5045.6%19219.7%
>85 Years00.0%00.0%120.1%00.00%
Sex
Female190037.3%110331.8%512056.7%36036.9%
Male239747.1%191055.1%285431.6%50051.2%
NS79215.6%45613.1%105611.7%11712.0%
Origin
EEA164832.4%93226.9%559562.0%36036.9%
NON-EEA344167.6%253773.1%343538.1%61763.2%
NS00.0%00.0%00.0%00.0%
Reporter
HP490296.3%334296.3%776986.0%89391.4%
Non-HP1783.5%1183.4%125413.9%848.6%
Not Specified90.2%90.3%70.1%00.0%
Table 3. Comparison of the relative occurrence frequency of each SOC. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
Table 3. Comparison of the relative occurrence frequency of each SOC. ALE—alemtuzumab; BAS—basiliximab; BEL—belatacept; THY—anti-T lymphocyte immunoglobulin for human use (rabbit).
System Organ ClassesTHYBASALEBEL
Blood and lymphatic system disorders8.6%5.2%7.8%3.7%
Cardiac disorders3.1%1.7%3.4%2.9%
Congenital, familial, and genetic disorders0.3%0.1%0.2%0.1%
Ear and labyrinth disorders0.1%0.1%0.4%0.3%
Endocrine disorders0.2%0.1%4.5%0.1%
Eye disorders0.5%0.5%1.3%1.1%
Gastrointestinal disorders4.3%4.6%4.4%4.0%
General disorders and administration site conditions11.5%8.2%11.9%8.8%
Hepatobiliary disorders2.5%1.7%1.4%0.3%
Immune system disorders10.7%12.5%2.9%8.5%
Infections and infestations15.4%20.3%11.1%23.1%
Injury, poisoning, and procedural complications7.3%7.7%6.0%15.0%
Investigations6.5%7.6%8.3%3.4%
Metabolism and nutrition disorders1.8%2.6%1.4%1.1%
Musculoskeletal and connective tissue disorders1.3%1.1%3.0%1.3%
Neoplasms benign, malignant, and unspecified (incl. cysts and polyps)3.6%3.7%2.7%4.0%
Nervous system disorders3.3%2.6%8.5%4.4%
Pregnancy, puerperium, and perinatal conditions0.1%0.2%0.3%0.3%
Product issues0.1%0.1%0.0%0.5%
Psychiatric disorders0.6%0.7%2.0%0.8%
Renal and urinary disorders4.3%7.47%2.6%5.4%
Reproductive system and breast disorders0.3%0.3%0.6%0.3%
Respiratory, thoracic, and mediastinal disorders5.6%4.2%4.8%3.7%
Skin and subcutaneous tissue disorders2.9%1.9%7.0%2.4%
Social circumstances0.1%0.0%0.3%0.1%
Surgical and medical procedures0.6%1.4%0.6%2.2%
Vascular disorders4.7%3.7%2.5%2.5%
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MDPI and ACS Style

Butuca, A.; Stoicescu, L.; Popa, M.L.; Dobrea, C.M.; Muntean, A.; Morgovan, C.; Pienar, C.; Gligor, F.G.; Ghibu, S.; Popa Ilie, I.R.; et al. Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study. J. Clin. Med. 2025, 14, 3409. https://doi.org/10.3390/jcm14103409

AMA Style

Butuca A, Stoicescu L, Popa ML, Dobrea CM, Muntean A, Morgovan C, Pienar C, Gligor FG, Ghibu S, Popa Ilie IR, et al. Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study. Journal of Clinical Medicine. 2025; 14(10):3409. https://doi.org/10.3390/jcm14103409

Chicago/Turabian Style

Butuca, Anca, Laurentiu Stoicescu, Mirela Livia Popa, Carmen Maximiliana Dobrea, Adriana Muntean, Claudiu Morgovan, Corina Pienar, Felicia Gabriela Gligor, Steliana Ghibu, Ioana Rada Popa Ilie, and et al. 2025. "Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study" Journal of Clinical Medicine 14, no. 10: 3409. https://doi.org/10.3390/jcm14103409

APA Style

Butuca, A., Stoicescu, L., Popa, M. L., Dobrea, C. M., Muntean, A., Morgovan, C., Pienar, C., Gligor, F. G., Ghibu, S., Popa Ilie, I. R., & Frum, A. (2025). Inefficiency Rates of Biological Immunosuppressive Induction Agents Used in Organ Transplantation: A Pharmacovigilance Study. Journal of Clinical Medicine, 14(10), 3409. https://doi.org/10.3390/jcm14103409

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