Published online Mar 27, 2026. doi: 10.4240/wjgs.v18.i3.117693
Revised: January 19, 2026
Accepted: February 3, 2026
Published online: March 27, 2026
Processing time: 91 Days and 3.9 Hours
Crohn’s disease-related perianal fistula (PFCD) is a common refractory compli
To evaluate the clinical efficacy and safety of loose seton drainage combined with oral Mahuang Shengma Decoction and external TCM (irrigation plus packing) for the treatment of simple PFCD.
A total of 60 patients with simple PFCD who were consecutively recruited from the Anorectal Department of The Affiliated Hospital of Xuzhou Medical Uni
The mean wound healing time in the treatment group was 35.2 ± 4.8 days, which was significantly shorter than that in the control group (42.5 ± 5.6 days) (independent samples t-test: t = 5.832, P < 0.001). Improvements in TCM syndrome scores and reductions in PDAI scores were more pronounced in the treatment group than in the control group (P < 0.05). No statistically significant differences were detected in the recurrence rate (10.0% in the treatment group vs 16.7% in the control group) or improvements in CDAI scores between the two groups (P > 0.05). During treatment, all patients underwent complete blood counts and liver and renal function tests at baseline, week 4, week 12, and the end of treatment. No serious AEs related to the protocol occurred in the treatment group. All liver and renal function parameters [including alanine aminotransferase (ALT), aspartate aminotransferase, serum creatinine (Cr), and estimated glomerular filtration rate] fluctuated within the normal reference range. Specifically, in the treatment group, the mean change from baseline to study end was 3.4 ± 0.5 U/L for ALT and 4.2 ± 1.0 μmol/L for Cr; neither intra-group nor inter-group comparisons reached statistical significance (all P > 0.05).
Oral Mahuang Shengma Decoction combined with external TCM therapy is effective for the treatment of simple PFCD, with distinct advantages in facilitating wound healing and alleviating local symptoms. It exhibits a favorable safety profile and can serve as an effective therapeutic option for simple PFCD, thus warranting further clinical adoption and application.
Core Tip: This study is the first to evaluate the efficacy of the comprehensive regimen of seton drainage combined with oral and external Traditional Chinese medicine (TCM) for the treatment of simple Crohn’s disease-related perianal fistula. The results demonstrate that this regimen can significantly shorten wound healing time, improve TCM syndromes and perianal symptoms, and has a favorable safety profile, thereby providing a novel integrated TCM and Western medicine therapeutic strategy for clinical practice.
- Citation: Zhang WF, Fan WT, Gao WW, Wu Z, Liu RR, Ruan CW. Crohn’s disease-related perianal fistula: A clinic research. World J Gastrointest Surg 2026; 18(3): 117693
- URL: https://www.wjgnet.com/1948-9366/full/v18/i3/117693.htm
- DOI: https://dx.doi.org/10.4240/wjgs.v18.i3.117693
Crohn’s disease-related perianal fistula (PFCD) is one of the most common perianal complications of Crohn’s disease (CD), with an incidence of approximately 20%-40%[1]. Its pathogenesis is closely linked to persistent intestinal inflammation, immune dysregulation, and perianal tissue damage. It is characterized by complex clinical manifestations, recurrent episodes, and delayed wound healing, which substantially compromise patients’ anal function and quality of life[2]. Currently, clinical management primarily relies on a combination of surgical intervention and biological agents. Among these agents, tumor necrosis factor-α (TNF-α) inhibitors, such as adalimumab have exhibited moderate efficacy in controlling intestinal inflammation and reducing the risk of recurrence. However, several limitations persist, including inadequate therapeutic response in some patients, delayed wound healing, and high healthcare expenditures[3].
Traditional Chinese medicine (TCM) has a long-standing and extensive experience in the management of anorectal diseases, particularly in regulating immune function, facilitating wound healing, and alleviating local symptoms[4]. In TCM theory, PFCD is classified under the categories of “perianal fistula” and “hemorrhoidal fistula”. Its core pa
Guided by the TCM principle of “simultaneous internal and external treatment”, this study adopted an integrated traditional Chinese and Western medicine approach-loose seton drainage combined with oral Mahuang Shengma Decoction and external TCM application-with the control group receiving adalimumab treatment alone. The primary aim was to evaluate the clinical efficacy and safety of this integrated approach in the management of simple PFCD and to provide a more cost-effective therapeutic option for clinical practice.
A total of 60 patients with simple PFCD who were consecutively recruited from the Anorectal Department of The Affiliated Hospital of Xuzhou Medical University between January 2021 and October 2024 were randomly allocated to either the treatment group or the control group, with 30 patients in each group.
The diagnosis of CD was established in accordance with the criteria outlined in the “consensus opinions on the diagnosis and treatment of inflammatory bowel disease” (2021, Beijing)[7], confirmed by colonoscopy, abdominal computed tomography, magnetic resonance imaging (MRI), and pathological biopsy. The diagnosis of perianal fistula was made based on the Guidelines for the Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Perianal Abscess and Perianal Fistula (2020 Edition)[8], and confirmed as a simple perianal fistula (single internal opening, single fistula tract, no branches, and no complex abscess formation) through digital rectal examination, anoscopy, and pelvic MRI.
Inclusion criteria: (1) Age 18-60 years, regardless of gender; (2) Meeting the aforementioned diagnostic criteria for both CD and simple perianal fistula; (3) Crohn’s Disease Activity Index (CDAI) score of 150-450 (indicating moderately active disease); (4) Perianal Disease Activity Index (PDAI) score ≥ 4; and (5) Voluntarily provided written informed consent and were able to comply with the follow-up protocol.
Exclusion criteria: (1) Complex perianal fistula (multiple internal openings, multiple fistula tracts, horseshoe-shaped perianal fistula, or other complex subtypes) or complicated by an acute perianal abscess; (2) Comorbidities including severe cardiac, hepatic, renal, or hematological diseases, or malignant tumors; (3) Pregnant or lactating females; (4) Known hypersensitivity to any component of Mahuang Shengma Decoction, adalimumab, or their excipients; (5) Prior use of other biological agents, immunosuppressants, or systemic glucocorticoids within 1 month before enrollment; and (6) Diagnosis of a psychiatric disorder or inability to comply with the treatment and follow-up protocols.
A total of 60 patients were randomly allocated to either the treatment group or the control group using a random number table generated by an independent statistician, with 30 patients in each group. The treatment group consisted of 18 males and 12 females, with a mean age of 38.5 ± 7.2 years, a mean disease duration of 3.2 ± 1.5 years, a mean CDAI score of 285.6 ± 42.3, and a mean PDAI score of 8.2 ± 2.1. The control group consisted of 16 males and 14 females, with a mean age of 39.2 ± 6.8 years, a mean disease duration of 3.5 ± 1.3 years, a mean CDAI score of 291.4 ± 38.6, and a mean PDAI score of 7.8 ± 2.3. No statistically significant differences were detected in demographic and clinical characteristics, including sex, age, disease duration, CDAI, and PDAI scores, between the two groups (all P > 0.05), indicating that the groups were comparable at baseline.
Control group: The control group received subcutaneous injections of adalimumab (Humira®, AbbVie Inc., North Chicago, IL, United States; specification: 40 mg/0.8 mL) at the standard dosage: 40 mg at week 0 and week 2, followed by 40 mg every 2 weeks for an additional 4 consecutive weeks.
Treatment group: In addition to the same adalimumab treatment as the control group, the treatment group underwent loose seton drainage, oral Mahuang Shengma Decoction, and external TCM therapy.
Surgical method: All patients underwent loose seton drainage performed by the same team of experienced surgeons. Under general anesthesia, a fistula probe was utilized to identify the direction of the fistula tract and the location of the internal opening. The skin from the external fistula opening to the perianal margin was incised, necrotic tissue was debrided, and a sterile rubber band was placed for loose seton drainage without tightening, with the aim of preserving perianal sphincter function. Routine disinfection and sterile dressing application were conducted postoperatively.
Oral TCM: Mahuang Shengma Decoction (formulation: Ephedrae Herba 6 g, Cimicifugae Rhizoma 6 g, Angelicae Sinensis Radix 10 g, Anemarrhenae Rhizoma 10 g, Scutellariae Radix 10 g, Polygonati Rhizoma 12 g, Paeoniae Radix Alba 10 g, Asparagi Radix 10 g, Cinnamomi Ramulus 6 g, Poria Cocos 15 g, Glycyrrhizae Radix et Rhizoma 6 g, Gypsum Fibrosum 15 g (decocted first), Atractylodis Macrocephalae Rhizoma 12 g, Zingiberis Rhizoma 6 g). The decoction was uniformly prepared by the TCM pharmacy of our hospital, with 200 mL per dose. It was administered warm twice daily (in the morning and evening), with one dose per day, for a consecutive 4-week course.
External TCM therapy: In the present study, “external TCM therapy” specifically refers to the combined application of two modalities: TCM irrigation and TCM gauze packing. Starting from postoperative day (POD) 2, an external TCM decoction (composed of Phellodendri Chinensis Cortex 30 g, Sophorae Flavescentis Radix 30 g, Taraxaci Herba 30 g, Galla Chinensis 15 g, Carthami Flos 10 g, Olibanum 10 g, and Myrrha 10 g) was decocted to a final volume of 500 mL and maintained at 40-45 ℃. The wound was irrigated with a sterile perianal irrigator for 10-15 minutes per session. Subsequent to irrigation, the wound was packed with sterile gauze soaked in the same TCM decoction once daily for a consecutive 4-week course.
Basic nursing: Both groups received standardized postoperative nursing care, including a light diet, maintenance of perianal cleanliness and dryness, avoidance of spicy and irritating foods and strenuous physical activity, and no other medications that could affect the therapeutic outcome were administered.
To address the dynamic and complex nature of PFCD, a comprehensive re-evaluation protocol was implemented to maintain the consistency of “simple perianal fistula” classification throughout the study.
Baseline confirmatory assessment: All eligible patients underwent a joint evaluation by experienced colorectal surgeons and radiologists prior to enrollment, which included a detailed digital rectal examination and pelvic high-resolution MRI (HR-MRI). Only patients confirmed to have a “simple perianal fistula” (with consistent results from both examinations) were included.
Dynamic follow-up re-evaluation: (1) Clinical trigger-based re-evaluation: If patients developed new clinical symptoms (e.g., exacerbated pain, altered discharge), abnormal physical examination findings (e.g., new induration or fistula opening), or a poor treatment response during follow-up, a repeat pelvic HR-MRI was promptly performed to reassess the fistula anatomy; and (2) Scheduled imaging re-evaluation: During the 6-month follow-up period, a planned repeat pelvic HR-MRI was performed at key efficacy assessment time points (i.e., post-treatment completion and primary study endpoint), regardless of changes in clinical symptoms, to objectively capture potential subclinical anatomical alterations.
Classification adjustment and data processing: If follow-up imaging revealed progression to a complex perianal fistula (e.g., multiple fistula tracts, high-positioned fistula, rectovaginal fistula, or concurrent abscess), the event was documented. In the data analysis, per-protocol set analysis was adopted, and such patients were categorized as having “classification evolution” for sensitivity analysis to assess the impact on the primary study conclusions.
Primary outcome measures: (1) Wound healing time: Defined as the duration from POD 1 to complete wound epithelialization, absence of exudate, and no pain; and (2) Recurrence rate: Patients were followed up for 6 months. Perianal fistula recurrence was defined as re-rupture and exudate from the external fistula opening, confirmed via digital rectal examination or pelvic MRI.
Secondary outcome measures: TCM syndrome score: A TCM syndrome scoring scale was developed based on the “standards for diagnosis and curative effect of TCM diseases and syndromes”[9], combined with the clinical features of PFCD. The items included perianal pain, purulent discharge, pruritus, perianal distension, loose stools, and fatigue. Each item was scored 0 (none), 1 (mild), 2 (moderate), or 3 (severe) points. Higher total scores indicated more severe clinical symptoms. Assessments were conducted at baseline and 4 weeks after treatment initiation.
PDAI: This index comprises 8 items, including pain, exudate, number of fistula tracts, and perianal function, with a total score ranging from 0 to 20 points. Higher scores indicate more severe perianal disease activity[10]. Assessments were conducted at baseline and 4 weeks after treatment initiation.
Crohn’s disease activity index: The simplified Harvey-Bradshaw Index was utilized, which includes 5 items: Diarrhea, abdominal pain, abdominal mass, complications, and extraintestinal manifestations. The total score ranges from 0 to 60 points, with a score ≥ 15 indicating active disease[11]. Assessments were conducted at baseline and 4 weeks after treatment initiation.
Safety outcomes: Adverse events (AEs), including gastrointestinal symptoms, rash, and abnormalities in liver or kidney function, were monitored throughout the treatment period. Routine blood tests, liver function tests, and renal function tests were conducted at baseline and every 2 weeks during treatment.
The sample size was calculated based on the primary outcome measure: Wound healing time. Based on previous clinical studies on PFCD treatment, the mean wound healing time of the control group (adalimumab monotherapy) was assumed to be 43.0 ± 6.0 days, and the treatment group was expected to have a 7-day shorter wound healing time (mean: 36.0 ± 5.0 days), representing a clinically meaningful difference. PASS 15.0 statistical software was used to perform the two-independent samples t-test calculation, with the following parameters: Α = 0.05 (two-tailed), power (1-β) = 0.80, a treatment group to control group ratio of 1:1, and a 20% dropout rate was accounted for. The calculated minimum sample size per group was 28 patients. Therefore, 30 patients were enrolled in each group (total n = 60) to ensure the study had adequate statistical power to detect the expected therapeutic effect.
Statistical analysis was performed using SPSS 26.0 software (IBM Corp., Armonk, NY, United States). Continuous data were presented as mean ± SD. Paired t-tests were used for intragroup comparisons (pre- vs post-treatment), and independent samples t-tests were used for intergroup comparisons. Categorical data were presented as n (%), and χ2 tests were used for intergroup comparisons. Fisher’s exact test was used when the expected frequency in any cell of the contingency table was < 5. A two-tailed P value < 0.05 was considered statistically significant.
The mean wound healing time in the treatment group was 35.2 ± 4.8 days, compared with 42.5 ± 5.6 days in the control group. The mean wound healing time was significantly shorter in the treatment group than in the control group (independent samples t-test: t = 5.832, P < 0.001).
During the 6-month follow-up period, 3 patients in the treatment group developed recurrence (recurrence rate: 10.0%), while 5 patients in the control group experienced recurrence (recurrence rate: 16.7%). No statistically significant difference was detected in the recurrence rate between the two groups (χ2 test: χ² = 0.652, P = 0.420).
At baseline, no statistically significant difference was observed in TCM syndrome scores between the two groups (independent samples t-test: t = 0.538, P = 0.593). After 4 weeks of treatment, TCM syndrome scores were significantly reduced in both groups compared with baseline (paired t-test: Treatment group: t = 16.327, P < 0.001; control group: t = 12.876, P < 0.001). Furthermore, the TCM syndrome score in the treatment group (2.1 ± 1.0) was significantly lower than that in the control group (4.3 ± 1.5) (independent samples t-test: t = 7.245, P < 0.001) (Table 1).
At baseline, no statistically significant differences were detected in either PDAI or CDAI scores between the two groups (PDAI: Independent samples t-test: t = 0.685, P = 0.496; CDAI: t = 0.579, P = 0.565). After 4 weeks of treatment, both PDAI and CDAI scores were significantly reduced in both groups relative to baseline (all P < 0.001; Table 2). Specifically, the PDAI score in the treatment group (2.3 ± 1.2) was significantly lower than that in the control group (4.1 ± 1.4) (independent samples t-test: t = 5.678, P < 0.001). In contrast, no statistically significant difference was observed in CDAI scores between the two groups (independent samples t-test: t = 0.452, P = 0.652). Detailed data on PDAI and CDAI scores are presented in Table 2.
No serious AEs (SAEs) were reported in the treatment group throughout the treatment period. Routine blood tests, liver function tests, and renal function tests were conducted at baseline, week 4, week 12, and the end of treatment in all patients. All liver and renal function parameters [including alanine aminotransferase (ALT), aspartate aminotransferase, serum creatinine (Cr), and estimated glomerular filtration rate] fluctuated within the normal reference range. Specifically, in the treatment group, the mean baseline ALT was 23.5 ± 4.2 U/L, and the mean value at the end of treatment was 26.9 ± 4.5 U/L, with a mean change of 3.4 ± 0.5 U/L; the mean baseline Cr was 68.3 ± 8.1 μmol/L, and the mean value at the end of treatment was 72.5 ± 8.3 μmol/L, with a mean change of 4.2 ± 1.0 μmol/L. No statistically significant differences were detected in either intra-group or inter-group comparisons (all P > 0.05). One patient in the treatment group experienced a transient, mild elevation of ALT (not exceeding 1.5 times the upper limit of normal), which returned to normal in subsequent re-evaluations without specific treatment and was considered related to disease activity or coincidental factors.
In the control group, 2 patients developed mild rashes, which resolved with symptomatic treatment and did not require adalimumab discontinuation. No SAEs were reported in either group. No statistically significant difference was detected in the incidence of AEs between the two groups (Fisher’s exact test: P = 0.150).
The cornerstone of PFCD management lies in controlling intestinal inflammation, facilitating perianal wound healing, preserving perianal function, and reducing the recurrence rate[12]. Loose seton drainage effectively debrides necrotic tissue within the fistula tract through rubber band drainage, minimizes damage to the perianal sphincter, and lays a favorable foundation for subsequent therapeutic interventions[13]. As a widely used biological agent in clinical practice, adalimumab mitigates intestinal inflammatory responses through the inhibition of TNF-α activity. However, its efficacy in facilitating the healing of local perianal wounds is limited, and it is associated with certain AEs and substantial healthcare costs[14].
TCM management of PFCD emphasizes the integration of “holistic syndrome differentiation and local treatment”. In the present study, the treatment group received the combination of oral Mahuang Shengma Decoction and external TCM therapy, which yielded favorable clinical outcomes. The underlying mechanisms may be as follows.
Mahuang Shengma Decoction is originally documented in Article 357 of Shanghan Lun (Treatise on Febrile Diseases): “After severe purgation on the sixth or seventh day of typhoid fever, the Cun pulse is deep and slow, the hands and feet are cold and clammy, the pulse in the lower part is not felt, the throat is uncomfortable, saliva mixed with blood and pus is expectorated, and diarrhea persists; this is intractable, and Mahuang Shengma Decoction is the main treatment”[15]. This formulation is characterized by sophisticated compatibility, integrating herbs with cold-warm properties and tonic-purgative effects: Ephedrae Herba, Cimicifugae Rhizoma, and Cinnamomi Ramulus disperse lung qi, relieve exterior symptoms, elevate yang, and unblock upper jiao qi movement; Scutellariae Radix, Gypsum Fibrosum, and Anema
Most patients with PFCD present with lung heat and spleen cold, characterized by the intermingling of cold and heat resulting from impairment of healthy qi (zhengqi) induced by chronic illness. By regulating the balance between cold and heat, invigorating the spleen, dispersing lung qi, nourishing blood, and promoting blood circulation, Mahuang Shengma Decoction improves patients’ general condition, regulates immune function, and fundamentally inhibits disease progression[16]. Contemporary pharmacological studies have demonstrated that Mahuang Shengma Decoction exerts anti-inflammatory, immunomodulatory, and intestinal mucosal barrier-protective activities[17]. Specifically, ephedrine in Ephedrae Herba inhibits the release of pro-inflammatory cytokines; baicalin in Scutellariae Radix exerts anti-inflammatory and antioxidant activities; and atractylodes polysaccharide in Atractylodis Macrocephalae Rhizoma regulates intestinal flora balance and enhances host immunity. These systemic activities likely contribute to the significant reduction in TCM syndrome scores observed in the treatment group.
External TCM therapy (irrigation plus packing) directly acts on the perianal wound bed, exerting effects of clearing heat and detoxifying, promoting blood circulation to resolve blood stasis, and debriding necrosis to induce granulation tissue formation[6]. The external TCM decoction used in the present study consists of Phellodendri Chinensis Cortex, Sophorae Flavescentis Radix, Taraxaci Herba, Galla Chinensis, Carthami Flos, Olibanum, and Myrrha: Phellodendri Chinensis Cortex and Sophorae Flavescentis Radix clear heat, dry dampness, detoxify, and relieve pruritus; Taraxaci Herba clears heat, detoxifies, reduces swelling, and dissipates masses; Galla Chinensis astringes bleeding and promotes wound healing; Carthami Flos, Olibanum, and Myrrha promote blood circulation, alleviate pain, and induce granulation tissue formation.
Collectively, these herbal components cleanse the wound bed, reduce exudate, alleviate pain, and facilitate granulation tissue proliferation and wound epithelialization[18]. Contemporary pharmacological studies have confirmed that these herbs possess antibacterial, anti-inflammatory, and tissue repair-promoting properties[19]: Berberine in Phellodendri Chinensis Cortex inhibits the growth of pathogenic bacteria (e.g., Staphylococcus aureus); matrine in Sophorae Flavescentis Radix attenuates local inflammatory responses; and taraxasterol in Taraxaci Herba accelerates wound healing. These local therapeutic effects are consistent with the study’s findings of a shorter wound healing time and lower PDAI scores in the treatment group.
The safety profile of the comprehensive treatment regimen is a major consideration. Although the long-term combined use of TCM decoctions theoretically carries potential risks of abnormalities in liver function, renal function, or electrolyte metabolism, the present study provides objective safety data through systematic and regular laboratory monitoring. The results demonstrated that within the specified treatment course, no clinically significant abnormalities were observed in the major liver and renal function parameters of the patients. This preliminary finding indicates that the oral TCM regimen, when combined with biological agents and surgery at the dosages and treatment course specified in the present study, has an acceptable safety profile.
However, it should be noted that the follow-up period of the present study is relatively short to medium-term. For extremely rare or long-term cumulative adverse reactions potentially associated with TCM, further verification is required through post-marketing surveillance with larger sample sizes or longer-term follow-up studies. We recommend that regular monitoring of liver and renal function should be incorporated into standard clinical care for any clinical practice involving long-term TCM treatment, to ensure patient safety.
The present study has initially validated the clinical efficacy of the comprehensive treatment regimen for PFCD. However, it is important to note that no rigorous pharmacoeconomic evaluation was performed in the present study. In the context of limited medical resources, particularly regarding the feasibility of its implementation in primary care settings, cost-effectiveness analysis of treatment regimens is of great importance.
In this context, the average daily cost of oral and external TCM in the comprehensive treatment regimen is generally considerably lower than that of biological agents. The mean wound healing time in the treatment group was 35.2 ± 4.8 days, compared with 42.5 ± 5.6 days in the control group. On the basis of surgery and biological agents, the adjunctive use of TCM can accelerate fistula healing, shorten the duration of biological agent administration, or reduce long-term recurrence rates. From a long-term pharmacoeconomic perspective, the initial additional cost of TCM is likely to be offset by the shortened duration of biological agent treatment and reduced reoperation rates, thereby conferring greater cost-effectiveness advantages. This “cost transfer” or “total cost savings” effect provides strong support for the potential implementation of the comprehensive treatment regimen in primary care settings.
Therefore, we propose that prospective cost-utility analysis studies should be conducted in the future to compare the long-term total medical costs and health outcomes of the “standard biological agent regimen” and the “integrated TCM-Western medicine comprehensive regimen” for the treatment of PFCD. Such studies will provide high-quality economic evidence to inform medical insurance reimbursement decisions and treatment selection in primary medical institutions.
The findings of the present study demonstrated that the treatment group was significantly superior to the control group in terms of wound healing time, improvement in TCM syndrome scores, and reduction in PDAI scores, indicating that the combination of oral Mahuang Shengma Decoction and external TCM therapy confers distinct advantages in facilitating perianal wound healing and alleviating local symptoms. This finding is consistent with those of previous studies[3,6], confirming the synergistic efficacy of integrated traditional Chinese and Western medicine in PFCD management: Oral TCM regulates systemic immunity and improves general health, while external TCM therapy directly targets the wound bed to facilitate healing. Their combination addresses both symptoms and root causes, thereby enhancing therapeutic efficacy.
Notably, no statistically significant differences in CDAI scores or recurrence rates were detected between the two groups. This may be attributed to the potent effect of adalimumab in controlling intestinal inflammation, which is the primary driver of PFCD progression and recurrence. In contrast, TCM therapy primarily targets local perianal symptoms and wound healing rather than systemic intestinal inflammation, which explains the absence of additional benefits on CDAI scores and recurrence rates in the short term. Furthermore, no SAEs were reported in the treatment group, indicating a favorable safety profile. Notably, TCM therapy is relatively cost-effective, rendering it particularly suitable for patients in primary care settings and those with limited economic resources.
The present study adopted a comprehensive therapeutic regimen integrating modern surgical intervention (loose seton drainage), biological agents, oral TCM decoction, and external TCM therapy (irrigation + packing). This combined strategy closely mimics the clinical complexity of PFCD management, with the goal of controlling active inflammation, facilitating fistula healing, and reducing recurrence through multi-targeted and multi-pathway synergistic effects. Our findings have initially demonstrated the potential advantages of this comprehensive regimen in improving fistula healing and reducing symptom severity.
However, we fully acknowledge an inherent limitation of the present study: Due to the complexity of the interventions, it is challenging to accurately quantify the relative contribution of each individual intervention (e.g., surgery, biological agents, oral TCM, external TCM therapy) to the overall therapeutic efficacy. This is a common challenge in real-world clinical studies involving complex interventions. The ultimate fistula healing may be the result of the combined effects of the following factors: (1) Surgery and biological agents: Serve as the “cornerstone” for controlling intestinal transmural inflammation and inducing deep fistula closure; (2) Oral Mahuang Shengma Decoction: May create a favorable systemic environment for local healing through systemic immune regulation, improving intestinal barrier function, and alleviating associated symptoms such as abdominal pain and diarrhea; and (3) External TCM therapy (irrigation + packing): May directly act on the local fistula, facilitating tissue repair from the inside out through mechanisms such as anti-inflammation, antibacterial activity, debriding necrosis, promoting granulation, and continuous drainage.
To further clarify the specific mechanisms and relative contributions of each component in the comprehensive treatment regimen, we propose the following future research directions: (1) Prospective factorial study design: A 2 × 2 × 2 factorial clinical trial could be designed in the future, randomly assigning patients to groups with different intervention combinations (e.g., group A: Surgery + adalimumab; group B: Surgery + adalimumab + oral TCM; group C: Surgery + adalimumab + external TCM; group D: Full regimen group). This design can more rigorously evaluate the independent efficacy of oral TCM and external TCM as adjunctive interventions; (2) Mechanism-exploratory studies: During the conduct of clinical studies, serum, tissue biopsy, and fecal samples could be collected from patients for multi-omics analyses (e.g., metabolomics, immunomics, gut microbiota metagenomics). By correlating different interventions with specific biomarker changes, objective biological evidence supporting the synergistic effect of the comprehensive treatment regimen can be provided from a systems biology perspective; and (3) Stepwise treatment and response prediction studies: Explore “treatment de-escalation” or “optimized sequencing” strategies based on patients' clinical characteristics (e.g., fistula activity, prior treatment history, serum biomarkers). For example, for specific patient subgroups, could a non-surgical regimen of biological agents + external TCM be attempted initially? This will facilitate the achievement of more precise and personalized treatment in the future.
The present study has several limitations. First, it is a single-center study with a relatively small sample size (n = 30 per group) and a short follow-up duration (6 months), which limits the generalizability of the findings and precludes the evaluation of long-term recurrence rates and perianal function. Second, the specific molecular mechanisms underlying the efficacy of Mahuang Shengma Decoction and external TCM therapy were not thoroughly elucidated. Third, the present study did not assess patient-reported outcomes (e.g., quality of life), which are critical for evaluating the clinical relevance of symptom improvement.
Future studies should utilize multi-center, large-sample randomized controlled trials with long-term follow-up to further validate the efficacy and safety of this therapeutic regimen. Furthermore, combining animal models and in vitro cell experiments will help elucidate the underlying molecular mechanisms (e.g., effects on pro-inflammatory cytokine expression or wound healing pathways), thereby providing a more robust theoretical basis for its clinical application. Incorporating patient-reported outcome measures (e.g., the Inflammatory Bowel Disease Questionnaire) will also enhance the comprehensiveness of efficacy assessment.
Oral Mahuang Shengma Decoction combined with external TCM therapy is effective for the treatment of simple PFCD, with distinct advantages in facilitating wound healing and alleviating local symptoms. It exhibits a favorable safety profile and can serve as an effective therapeutic option for simple PFCD, thus warranting further clinical adoption and application.
We acknowledge Mr. Peng He, biostatistician, for his valuable guidance on the statistical analysis of this manuscript.
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