A systematic review of treatment strategies to combat acute and chronic rejection episodes in vascularized composite allotransplantation

Background: Vascularized composite allotransplantation (VCA) offers unique reconstructive solutions for severe tissue loss, restoring form and function. Acute and chronic rejection remains a significant barrier, with acute episodes occurring in most recipients and chronic rejection persisting as the leading cause of graft failure. Unlike solid organ transplantation, VCA involves highly immunogenic tissues, like skin and mucosa, making rejection more frequent and challenging to manage.

Methods: A systematic review was conducted following PRISMA 2020, searching PubMed/MEDLINE, EMBASE, and Web of Science for original human VCA studies reporting immunosuppressive protocols and outcomes in acute or chronic rejection. Quality was assessed using the Newcastle–Ottawa Scale and Level of Evidence; extracted data included demographics, regimens, rejection episodes, treatments, and graft survival.

Results: Fourty-six studies (136 recipients) met inclusion criteria: upper extremity (n=69; 51%), face (n=33; 24%), abdominal wall (n=33; 24%), scalp and penile (each n=1; 0.7%). Acute rejection occurred in 81/136 (60%) within year 1, most often at POW 1–2 (n=52), 5–12 (n=42), and 13–52 (n=30). Severity was Banff grade I (n=49; 36%), II (n=73; 54%), III (n=50; 37%), and severe IV (n=1; 0.7%). Common symptoms included skin lesions (n=43; 32%), edema (n=32; 24%), erythema (n=29; 21%), and rash (n=15; 11%), with some experiencing numbness (n=4; 2.9%), tingling (n=5; 3.7%), or burning sensations (n=5; 3.7%). Corticosteroids were the mainstay (n=98; 72%)—methylprednisolone (n=31; 23%), clobetasol (n=15; 11%), and prednisone (n=11; 8.1%); tacrolimus was used in 49 (36%), including topical in 29 (21%). Other immunosuppressants included antithymocyte globulin (n=19; 14%), alemtuzumab (n=11; 8.1%), mycophenolate mofetil (n=11; 8.1%), and rituximab (n=6; 4.4%); basiliximab (n=4; 2.9%), sirolimus (n=2; 1.5%), and plasmapheresis (n=4; 2.9%) were used selectively. Monotherapy was used in 42 episodes, and dual therapy in 51, most commonly methylprednisolone plus topical tacrolimus (n=26).

Conclusion: This review underscores the ongoing challenge of rejection in VCA and the need for improved treatment strategies, with corticosteroids, calcineurin inhibitors, and mycophenolate mofetil remaining standard while emerging biologicals offer promise. Acute rejection is often manageable yet threatens graft survival, whereas chronic rejection is less reported, likely under-recognized and harder to treat, underscoring need for novel immunomodulators, standardized protocols, and prevention to improve outcomes.

GRAPHICAL ABSTRACT

Graphical Abstract.

1 Introduction

Vascularized composite allotransplantation (VCA) is a life-changing procedure that offers potential restoration of lost function and appearance for patients with severe tissue defects. However, rejection remains a major problem, limiting the long-term success and widespread use of VCA. Unlike solid organ transplants (SOT), VCA includes multiple tissue types such as skin, mucosa, muscle, and nerves, making rejection more frequent and difficult to control (1–5).

Among all VCA types, face transplants experience the highest rejection rates, possibly due to the high proportion and immunogenicity of skin and mucosal tissue (6, 7). Acute rejection is most commonly observed within the first year post-transplant, with over 85% of recipients experiencing at least one episode, often within the first 3 to 6 months, though some early events may occur within 30 days. Chronic rejection, on the other hand, tends to develop after the first year, manifesting as progressive vasculopathy, fibrosis, or functional decline of the graft over time (8–10). Overall, chronic rejection is more rare and considered the leading cause of long-term graft failure, with 10-20% of face and upper extremity VCA recipients experiencing chronic rejection (2, 11, 12). Therefore, chronic rejection has been identified as the leading cause of graft loss and retransplantation (13–15). In summary, the high risk of rejection poses a significant barrier that hinders widespread clinical adoption of VCA and varies in certain types of VCA (16, 17).

Treating rejection in VCA depends on the severity and type of rejection. Mild acute rejection is usually managed with increased doses of corticosteroids, while more severe cases may require additional immunosuppressive drugs like tacrolimus (TAC) or mycophenolate mofetil (MMF) (10, 18). In cases of chronic rejection, effective treatment options remain limited. Chronic rejection in VCA lacks an established treatment and is often diagnosed alongside graft deterioration. Therapies like intravenous immunoglobulin (IVIG), plasmapheresis, and conversion to sirolimus have shown limited success, underlining the need for novel therapies and additional research to fill this gap in the literature (1, 19).

Overall, treating rejection in VCA remains challenging, limiting the widespread applicability of VCA surgery. Therefore, consolidation of existing literature is necessary to identify knowledge gaps. This could provide helpful insights for both VCA providers and patients and pave the way for further research. To fill this gap, this systematic review aims to explore current and emerging treatment strategies for rejection in VCA recipients.

2 Methods

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Given the heterogeneity in study designs, patient cohorts, and outcome measures, a narrative synthesis was chosen. The full study protocol is accessible at PROSPERO (CRD420251027621).

2.1 Systematic search

A comprehensive literature search was conducted across PubMed/MEDLINE, EMBASE, and Web of Science databases, covering studies published up to November 30, 2024, that focused on rejection treatment in vascularized composite allotransplantation (VCA) recipients. The search strategy combined two key components using the Boolean operator “AND” to refine the selection process. The first component included VCA-related terms, such as “vascularized composite allotransplantation”. The second component targeted rejection and immunosuppression-related terms, including “acute rejection”, “chronic rejection”, and “Banff classification”. MeSH-Terms as well as synonyms of each were applied accordingly. To ensure a comprehensive overview, cross-referencing of fitting studies was performed. The full search strategy is provided in the Supplementary Table. Studies were eligible for inclusion if they provided original data on treatment strategies for acute or chronic rejection in human VCA recipients, covering interventions such as corticosteroids, biologics, plasmapheresis, and novel immunomodulatory therapies. Only studies that reported detailed treatment protocols and outcomes were considered. Exclusion criteria encompassed studies focusing solely on VCA feasibility, anatomy, or surgical techniques without rejection treatment data, as well as non-VCA transplant studies, non-English publications, and systematic reviews or meta-analyses reporting non-original data. All non-peer reviewed studies were excluded. Furthermore, two cases of facial retransplantation were found in literature but not included in qualitative analysis for better comparability amongst other VCA cases (15, 20). In cases where multiple studies reported on the same patient cohort, the most comprehensive publication—detailing immunosuppressive strategies and the longest follow-up—was selected.

Title and abstract screening were independently conducted by two reviewers (T.S. and T.N.), followed by a full-text review of eligible studies. Any discrepancies were resolved through discussion with a third reviewer (L.K.). The full study selection process is outlined in Figure 1 (PRISMA 2020 flowchart).

Figure 1

Figure 1. PRISMA 2020 flowchart highlighting study workflow.

2.2 Quality assessment

The methodological quality of human studies was evaluated using the Newcastle-Ottawa Scale (NOS) and Level of Evidence (LOE) frameworks. The NOS system assessed three key domains: selection of study cohorts, comparability of study groups, and assessment of outcomes/exposures, with a higher NOS score indicating lower risk of bias. The LOE system ranked studies based on methodological rigor, classifying systematic reviews and randomized controlled trials (RCTs) as LOE I, while retrospective cohort studies were categorized as LOE III-IV. Further quality assessment details are presented in Supplementary Tables 1, 2.

2.3 Data extraction

In the blinded, dual-review process, the following variables were extracted for human studies: first author, Digital Object Identifier, study title, year of publication, region of publication, institution of transplantation, sample size, recipient sex and age, donor sex and age, type of transplanted VCA, length of follow-up, indication for VCA, induction and maintenance immunosuppressive regimens, presence of rejection (yes/no/acute/chronic), Banff classification of rejection, treatment of rejection episodes (corticosteroid therapy, immunosuppressive modifications, biologic agents, plasmapheresis, extracorporeal photopheresis, donor-specific antibody removal, and adjunct therapies), and overall graft outcome.

Treatment outcomes for acute rejection were categorized as successful if the rejection episode was ultimately reversed and the graft was preserved, regardless of whether multiple lines of therapy or protocol modifications were required. Treatment was defined as unsuccessful only if the rejection episode progressed to total graft loss despite therapeutic intervention. Temporary histological persistence that subsequently resolved with treatment escalation was considered part of a successful management course.

3 Results

A total of 1,150 articles were screened, with 46 (4.0%) meeting the inclusion criteria. Due to the limited number of VCAs performed globally and overlapping reports on the same cases, studies were grouped by individual VCA cases. Year of publication spanned from 1999 to 2024. Case reports (n = 25; 54%) and case series (n = 18; 39%) were the most common study types. The mean (± SD) NOS was 5.1 (± 0.3), indicating low to moderate methodological quality.

3.1 Patient demographics

Overall, n = 136 (100%) VCA recipients were included. The recipient cohort was predominantly male, with 73% (n = 99) male patients. In donors, n = 51 (38%) were male, whereas gender was not declared in n = 78 (57%) cases. Recipient age ranged from 1 to 69 years, with a mean (± SD) of 39.5 (± 12.9) years. Donor age ranged from 8 to 65 years, with a mean (± SD) of 37.3 (± 12.9) years. The mean (± SD) follow-up period was 35.6 (± 34.4) months and ranged from 1.5 to 228 months. Upper extremity was the most common VCA type (n = 69; 51%), including bilateral procedures in n = 28 cases (21%), followed by face (n = 33; 24%) and abdominal wall transplants (n = 33; 24%) as well as n = 1 (0.7%) case of scalp and penile transplantation, each. More details are provided in Table 1.

Table 1

Table 1. Demographical details of patient cohort.

3.2 Indications for VCA

The most common indication for VCA was trauma (n = 53; 39%), including n = 13 (9.6%) ballistic injuries, followed by gastrointestinal disorders (n = 30; 22%), such as Gardner Syndrome (n = 5; 3.7%) and Hirschsprung disease (n = 3; 2.2%). Here, VCA was typically required due to abdominal wall failure following repeated surgical intervention. Burn injuries accounted for n = 20 (15%) VCAs, including n = 12 (8.8%) electrical burns. Other indications included amputations (n = 7; 5.1%), animal bites (n = 6; 4.4%), and conditions such as osteoradionecrosis (n = 1; 0.7%), neurofibromatosis type I (n = 1; 0.7%), or irreversible tissue ischemia (n = 1; 0.7%). Further information is provided in Table 1.

3.3 Immunosuppressive regimens

Induction therapy included antithymocyte globulin (ATG) in n = 74 (46%) cases, followed by MMF in n = 49 cases (31%) and TAC in n = 48 cases (30%). Steroids (STR) were administered in n = 66 cases (42%), primarily as prednisone (n = 35; 22%) and methylprednisolone (n = 24; 15.0%). Further induction agents included alemtuzumab (n = 45; 28%), basiliximab (n = 16; 10%), and belatacept (n = 4; 2.5%), with smaller numbers receiving cyclophosphamide, azathioprine, donor bone marrow cells (each n = 2; 1.3%), and rituximab (n = 1; 0.6%).

Maintenance therapy varied from induction in dosage and drug composition. It predominantly included TAC (n = 133; 98%), STR (n = 94; 69%), and MMF (n = 92; 68%). The most common STR was prednisone (n = 63; 46%). Further maintenance agents were sirolimus (n = 15; 11%), azathioprine (n = 4; 2.9%), belatacept (n = 4; 2.9%), everolimus (n = 2; 1.5%), extracorporeal photopheresis (n = 4; 2.9%), extracorporeal photochemotherapy (n = 2; 1.5%), basiliximab (n = 1; 0.7%), and IL-2 therapy (n = 2; 1.5%). Further details are provided in Table 2, Figure 2.

Table 2

Table 2. Immunosuppressive baseline regimen of patient cohort.

Figure 2

Figure 2. Drug combinations for graft maintenance and acute rejection treatment. Legend: The most common maintenance immunosuppression combinations were TAC + MMF + PDN (48 treatments), followed by SRL + MMF + PDN (4 treatments) and TAC monotherapy (3 treatments). The most common drug combination in acute rejection treatment was MPED Pulse/Bolus monotherapy (42 episodes), followed by MPED + topical TAC (26 episodes) and MPED with an increase in baseline TAC (25 episodes). TAC, Tacrolimus; MMF, Mycophenolate Mofetil; PDN, Prednisone; SRL, Sirolimus; MPED, Methylprednisolone.

Frequency, Symptoms and Treatment of Acute Rejection Episodes.

A total of n = 219 rejection episodes were reported, of which n = 218 were reported as acute. Most patients experienced one (n = 40; 29%), two (n = 19; 14%), or three (n = 17; 13%) rejection episodes. A small subset had four to six rejection episodes (n = 4 each; 2.9%). In selected cases, seven (n = 3; 2.2%) or more than eight rejection episodes (n = 2; 1.5%) were reported. Most commonly, rejection first occurred later than postoperative week (POW) 52 (n = 52), followed by POW 5-12 (n = 42) and POW 13-52 (n = 30). Early rejection within the first four weeks was observed in n = 13 cases (22).

Banff grade I rejection was reported in n = 49 (36%) cases. However, Banff grade II (n = 73; 54%) and grade III (n = 50; 37%) were the most frequent. Banff grade IV rejection was reported in n = 1 (0.7%) case.

Symptoms of acute rejection included skin lesions (n = 43; 32%), edema/swelling (n = 32; 24%), erythema (n = 29; 21%), and rashes (n = 15; 11%). Further signs were sensory changes such as numbness (n = 4; 2.9%), tingling (n = 5; 3.7%), burning sensations (n = 5; 3.7%), or pain (n = 7; 5.1%).

Overall, STR were the mainstay of acute rejection treatment, administered in n = 98 (72%) cases, with methylprednisolone (MPED) (n = 31; 23%), clobetasol (n = 15; 11%), and prednisone (PDN) (n = 11; 8.1%) being the most common agents. TAC was administered in n = 49 (36%) cases, with n = 29 (21%) receiving topical applications. Further immunosuppressive therapies included ATG (n = 19; 14%), alemtuzumab (n = 11; 8.1%), MMF (n = 11; 8.1%), and rituximab (n = 6; 4.4%), while basiliximab (n = 4; 2.9%), sirolimus (n = 2; 1.5%), and plasmapheresis (n = 4; 2.9%) were used in selected cases. Additional agents such as immunoadsorption (n = 3; 2.2%), extracorporeal photochemotherapy (n = 2; 1.5%), bortezomib (n = 1; 0.7%), eculizumab (n = 1; 0.7%), and pimecrolimus (n = 1; 0.7%) were employed. Details on individualized rejection therapies are depicted in Table 3 as well as data on frequency of different drug regimens in Figure 2.

Table 3

Table 3. Rejection frequency, Banff classification, signs of rejection and treatment of rejection in patient cohort.

3.4 Success rates of acute rejection treatment

Success of rejection treatment was defined as preservation of the graft, even if the immunosuppressive treatment regimen was changed during that rejection episode. Unsuccessful treatment was, in turn, defined as graft loss. Out of 136 VCA cases, rejection treatment was reported as successful in n = 91 (67%) cases, while graft loss was reported in n = 12 (8.8%) cases.

Rejection treatments reported in face VCAs had a success rate of 100% with treatment durations of 3 days to 8 weeks. In all (n = 41; 30%) but n = 1 (0.7%) rejection, STR was used. Here, n = 5 (3.7%) cases received STR as single treatment, n = 4 (2.9%) in combination with ATG, or in combination with ATG, TAC, topical TAC and MMF in n = 3 (2.2%) cases.

In upper-extremity VCAs, n = 54 (40%) cases were reported as successful, while n = 9 (6.6%) were unsuccessful and resulted in graft loss. Of these, n = 4 (2.9%) discontinued immunosuppressive therapy owing to infection and VCA-unrelated surgical interventions. In all other cases (n = 45; 33%), STR, topical TAC and ATG were used. STR single therapy was the most frequent (n = 22; 16%) followed by STR combined with topical TAC (n = 10; 7.4%) or STR combined with ATG (n = 5; 3.7%). Treatment duration ranged from 2 days to 3 months.

In abdominal-wall transplants, all (n = 33; 24%) rejections were treated either via STR single therapy, STR + alemtuzumab, or STR + ATG. Treatment duration ranged from 3 to 5 days and no graft losses were reported.

At last, rejection in scalp VCA (n = 1; 0.7%) was successfully treated with STR therapy, whereas rejection in penile VCA (n = 1; 0.7%) was treated by STR and ATG dual therapy over 3 days. Full insights on acute rejection treatment are provided in Table 3.

3.5 Chronic rejections

Despite more than two decades of clinical experience in VCA, a universally accepted definition or staging system for chronic rejection (CR) is still lacking. Consensus efforts remain focused on acute, skin-predominant changes, leaving late fibrotic and vasculopathic lesions insufficiently characterized (22, 23). The few systematically documented cases illustrated that CR is most likely under-recognized rather than rare. At present, no validated treatment algorithm exists.

A clinical descriptive series of CR from Krezdorn et al., reviewed longitudinal protocol biopsies from seven face-transplant recipients (24). Three patients developed progressive, clinically subtle changes - premature ageing, telangiectasia along suture lines, tightening of the skin - that correlated with distinctive histology: epidermal thinning, follicular plugging, papillary-dermal sclerosis and a shift of type-I collagen towards the superficial dermis. Gene-expression profiling pointed to AP-1-pathway activation (c-Fos/JunB) as a putative driver of fibrosis. Notably, microvascular intimal hyperplasia was absent, underscoring that cutaneous CR might evolve independently.

Current therapeutic evidence after chronic rejection is constrained to two cases of facial retransplantation (15, 20). Both patients lost their first VCA graft due to chronic rejection. One patient developed Grade 2/3 Banff rejection on day 14, while the other presented with Grade III chronic antibody-mediated rejection involving erythema and mucosal tissues.

After retransplantation, acute rejection occurred and was successfully managed with methylprednisolone bolus therapy, supplemented by eculizumab in the first patient and alemtuzumab in the second patient due to refractory mucosal involvement.

In sum, the available evidence portrays chronic rejection in VCA as a heterogeneous, slowly evolving entity that is clinically subtle, histologically diverse and, to date, largely untreatable except by retransplantation.

4 Discussion

Acute and chronic rejection remain the central challenges to the long-term success of VCA. Despite surgical and medical advancements, these forms of rejection continue to limit broader clinical adoption and underline the need for optimized immunosuppressive strategies and targeted therapies (1, 25–27).

In our study, acute rejection was common, with most patients experiencing multiple episodes that were generally well-managed using corticosteroids, tacrolimus, and adjunct therapies, resulting in high success rates and relatively low rates of graft loss. In contrast, chronic rejection was rarely reported, poorly characterized, and remains a largely untreatable challenge in VCA, underscoring the need for further research to improve long-term outcomes.

Focusing on acute rejection, our results were in line with current literature. STR-based therapies remained the frontline strategy for acute rejection episodes in VCA, as confirmed by Alhefzi et al., who reported resolution in up to 70–80% of cases across different graft types, while also noting that inadequately treated acute rejection could contribute to chronic graft failure (1). Beyond STR, adjunct agents such as ATG, MMF, and TAC have been employed in cases of STR-resistant rejection or as combined therapy to intensify immunosuppression. Fischer et al. confirmed that acute rejection episodes were generally STR-responsive, with treatment success in over 85% of cases following timely intervention. The authors highlighted the importance of optimized triple immunosuppressive therapy to prevent recurrence (6). Hautz et al. described that acute rejection was often treated not only with systemic STR but also with adjunctive topical agents such as topical TAC, which allowed localized immunosuppression directly at the graft site while reducing the risks associated with systemic drug exposure (28). This was further confirmed by recent studies, demonstrating that the vast majority —over 80%— of VCA rejection episodes in hand and face transplants were successfully controlled with high-dose STR and immunosuppressive adjustments (e.g. alemtuzumab, donor bone marrow), and patient specific considerations such as human leukocyte antigen (HLA) matching (29). Interestingly, experimental approaches, such as localized tacrolimus delivery via intra-graft injection or hydrogel-eluting platforms, have shown promise in in extending graft survival up to 200 days in animal models while avoiding systemic side effects (30, 31). Fisher et al. evaluated emerging biologic and cell-based therapies in VCA, including regulatory T cell–based tolerance strategies, and proposed these approaches as promising avenues to enhance long-term graft survival while potentially reducing or even eliminating the need for lifelong systemic immunosuppression (32). At last, Etra et al. discussed the emerging use of targeted therapies, including antibody-based agents and costimulatory blockade, particularly in sensitized or complex VCA recipients, though these approaches remained largely experimental (33). Despite the overall success of corticosteroid-based therapies in treating acute rejection in VCA, approximately 20–30% of episodes do not respond adequately to standard immunosuppression. This observation suggested the involvement of additional, possibly unexplored, alloimmune pathways that contribute to treatment-resistant rejection. This underscored the need for further research to elucidate these underlying immunologic mechanisms and to develop more targeted, individualized treatment strategies (1, 25, 26, 34, 35).

In contrast to acute rejection, chronic allograft deterioration in VCA lacks a standardized consensus definition, which remains a critical barrier to effective management. Our review highlights that chronic rejection is characterized in the literature by subtle, insidious evolution—manifesting as late vasculopathy (myointimal hyperplasia) and tissue fibrosis (sclerosis, adnexal atrophy)—yet there is currently no unified diagnostic algorithm or grading system comparable to the Banff criteria for acute rejection (22). This definitional ambiguity directly impacts clinical practice: we found no established therapeutic protocols for chronic rejection. While early acute rejection is successfully managed with standardized pulse corticosteroids and topical immunosuppression, treatment for chronic rejection is highly heterogeneous and largely empirical, often relying on salvage therapies (e.g., plasmapheresis, lymphoid depletion) with inconsistent success (9, 36). Chronic rejection thus appears to represent irreversible graft injury resulting from cumulative or inadequately controlled immune responses. Future studies should focus on the development of standardized diagnostic criteria and the establishment of evidence-based treatment protocols, rather than relying on ad hoc management of graft failure (29, 37, 38). Ultimately, this might also improve or facilitate finding appropriate VCA donors (39).

In summary, our findings support a pragmatic, stepwise clinical protocol for VCA rejection management that can be tailored to the severity and biology of rejection in individual recipients. However, given the descriptive nature of the available literature and variability in reporting and treatment strategies, these observations should be interpreted cautiously and cannot be taken as establishing a definitive, universally applicable protocol.

High success rates of corticosteroid-based treatment in acute rejection episodes likely reflect the importance of prompt recognition and early intervention, which are key to preserving graft function. However, despite these successes, approximately one-fifth of acute rejection episodes did not respond adequately to standard immunosuppression, suggesting the existence of additional, as-yet unexplored, alloimmune pathways. This underscores the need for further research to better understand these complex mechanisms and develop more targeted, individualized therapies to improve long-term outcomes. For steroid-resistant episodes, our data support combination immunosuppressive strategies involving agents such as ATG, MMF, and tacrolimus, which have shown efficacy in intensifying treatment. Because of the anatomic accessibility of VCA grafts, clinical practice should readily incorporate topical immunosuppression like tacrolimus as an adjunct for skin-predominant rejection to minimize systemic toxicity. Furthermore, escalation to B-cell targeted therapies (e.g. Rituximab), plasmapheresis, IVIG or proteasome inhibitors (e.g. Bortezomib) should be considered, particularly in complex or antibody-mediated rejections. Finally, for VCA patients, medication adherence and close communication with transplant teams are critical to ensuring timely detection and management of rejection, as salvage therapies have shown very limited efficacy in chronic graft rejection. Individuals at higher immunologic risk or with a prior history of rejection should be particularly diligent in attending follow-up appointments and maintaining ongoing dialogue with their care providers, as early therapeutic adjustments can significantly improve long-term outcomes. Ultimately, effective rejection management is essential to safeguarding the long-term success of VCA and ensuring optimal outcomes of VCA surgery over time.

5 Limitations

Despite the comprehensive approach of this systematic review, several limitations must be acknowledged. First, the heterogeneity of study designs, patient cohorts, and treatment protocols limited the feasibility of a quantitative meta-analysis. To address this, we employed a structured narrative synthesis and strictly categorized interventions to identify consistent clinical patterns across diverse centers and surgeries, thereby providing a consolidated overview of rejection management strategies in this rare field. Many included studies were case reports or small case series, reducing generalizability and statistical robustness. However, given the prevalence of VCA, these reports constitute the entirety of the available evidence base, and by aggregating these data, our study offers one of the largest cumulative datasets currently available. Since a number of studies grouped hand, wrist, and more proximal reconstructions indiscriminately, these procedures were pooled under the umbrella term “upper-extremity VCA,” which may mask anatomical differences. We tried to mitigate this by focusing our analysis on systemic immunological outcomes rather than functional metrics, as rejection mechanisms are largely independent of the specific level of amputation. Reporting of chronic rejection was highly inconsistent regarding surveillance biopsies and histological terminology. We addressed this by applying a standardized definition of ‘treatment success’ (graft salvage vs. loss) across all studies, ensuring a clinically relevant endpoint that remains valid despite histological variability. However, the heterogeneity in our dataset still reinforces the critical need for evidence-based guidelines to standardize both the diagnosis and therapeutic management of chronic rejection in VCA. In this context, establishing a multinational, multicenter outcomes database with harmonized definitions and reporting standards would be crucial to facilitate knowledge transfer and enable better treatment and outcome comparability across VCA centers. Additionally, the reliance on retrospective data introduces potential publication bias favoring positive outcomes. We attempted to minimize this by conducting a comprehensive search strategy, which included reports of graft failure and explicitly discussing complications, providing a more balanced view of therapeutic risks. While the exclusion of non-English publications may have omitted some data, our search strategy covered all major international VCA centers, ensuring that the most clinically relevant cases were captured. Furthermore, key immunological variables such as HLA mismatches, donor-specific antibodies (DSA), and panel reactive antibody (PRA) levels were reported too inconsistently to permit meaningful extraction or comparison, and this lack of standardized immunologic data represents an additional limitation of the available literature. Similarly, the inconsistent and often non–episode-specific reporting of rejection symptoms, together with the lack of standardized data on the timing of initial treatment response and subsequent therapy escalation, prevented meaningful correlation of clinical manifestations and treatment kinetics with early versus late rejection, representing an additional limitation of the current evidence base. Moreover, because many studies reported immunosuppressive regimens incompletely or with insufficient detail, only the most commonly used agents could be meaningfully synthesized, limiting the inclusion of experimental or less frequently used therapies and underscoring the need for more structured and standardized reporting in future VCA research. Additionally, because QoL and psychosocial outcomes were reported only sparingly and without standardized tools, we explicitly note that future research should systematically evaluate QoL impacts to provide a more holistic understanding of long-term patient outcomes. Importantly, this gap extends beyond patient-reported measures like the effects of rejection episodes to broader psychosocial dimensions—such as public reception and acceptance—that are relevant for long-term implementation (40). Finally, meaningful statistical comparison was not feasible due to substantial heterogeneity in study design, reporting standards, outcome definitions, follow-up duration, and immunosuppressive regimens, and this limitation highlights the urgent need for more standardized, comprehensive, and longitudinal data to enable the type of robust analyses required to advance evidence-based rejection management.

6 Conclusion

This systematic review demonstrates that while acute rejection in VCA is frequent, it is often responsive to a standardized, stepwise protocol of pulse corticosteroids and topical adjuncts, although the available evidence is largely retrospective and heterogeneous and therefore does not yet allow firm comparative conclusions on the relative effectiveness of different strategies. Chronic rejection remains a critical and underexplored barrier, likely underdiagnosed due to the absence of standardized diagnostic criteria and consequently limited therapeutic options once it is established. Consequently, long-term graft survival currently relies on the prevention of chronic deterioration through early rejection management and rigorous surveillance rather than rescue. Future efforts should prioritize standardizing diagnostic definitions and developing targeted therapies to bridge this gap, ultimately supporting the broader and safer adoption of VCA.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Author contributions

LK: Project administration, Supervision, Writing – review & editing, Methodology, Writing – original draft, Conceptualization, Data curation, Validation. TN: Data curation, Investigation, Conceptualization, Writing – review & editing, Validation, Writing – original draft, Visualization, Project administration. TS: Writing – original draft, Software, Data curation, Conceptualization, Investigation, Methodology, Writing – review & editing, Validation, Formal analysis. GH: Resources, Conceptualization, Validation, Supervision, Writing – review & editing, Writing – original draft. RM: Writing – original draft, Investigation, Visualization, Formal analysis, Validation, Data curation, Writing – review & editing. MH: Supervision, Writing – review & editing, Writing – original draft, Resources, Funding acquisition. CC: Writing – original draft, Validation, Writing – review & editing. AL: Conceptualization, Resources, Writing – review & editing, Supervision, Validation, Writing – original draft.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1733221/full#supplementary-material

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