Abstract
Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease requiring effective treatment. This study aimed to evaluate the efficacy and safety of Kangfuxin liquid enema combined with adalimumab compared to adalimumab monotherapy in patients with UC. Methods: This retrospective cohort study included 240 UC patients treated between June 2022 and January 2024. Patients were divided into a combination therapy group (CT, adalimumab + Kangfuxin enema, n = 123) and a monotherapy group (MT, adalimumab alone, n = 117). We assessed clinical efficacy, adverse reactions, quality of life, serum inflammatory cytokines (interleukin-1 beta [IL-1β], interleukin-8 [IL-8], tumor necrosis factor-alpha [TNF-α]), endoscopic scores (Mayo, Baron), histologic score (Geboes), oxidative stress indicators (superoxide dismutase [SOD], malondialdehyde [MDA]), and intestinal barrier indicators (diamine oxidase [DAO], D-lactate) before and after 8 weeks of treatment. Results: Overall response rate observed in the CT cohort (88.62%) significantly exceeded that of the MT cohort (73.50%, P = 0.003). Mucosal healing rates were 56.10% vs. 32.48% (P < 0.001). Endoscopic remission rates were 65.04% vs. 47.01% (P = 0.005). Post-treatment inflammatory factor levels were decreased in the CT group (all P < 0.001). Oxidative stress and intestinal barrier markers also improved more in the CT group (all P < 0.001). Moreover, patient-reported quality of life (assessed by IBDQ-32) improved significantly more in the CT group (P < 0.001). Adverse reaction incidence (8.94% vs. 23.94%, P = 0.002) was decreased in the CT group. Conclusion: Combining Kangfuxin liquid enema and adalimumab was more effective and safer than adalimumab alone in the treatment of ulcerative colitis.
Keywords: Kangfuxin liquid, adalimumab, ulcerative colitis, combination therapy
Introduction
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease. It primarily affects the colonic mucosa, causing symptoms such as persistent diarrhea, rectal bleeding, and abdominal pain. The disease course is often unpredictable, with alternating periods of remission and flare-up. This pattern imposes a substantial burden on patients’ quality of life and poses a long-term risk for complications, including colorectal cancer [1-3].
UC pathogenesis involves complex interplay among genetic predisposition, environmental influences, gut microbiota, and a dysregulated immune response [4]. A key feature is excessive activation of the mucosal immune system. This leads to the overproduction of proinflammatory cytokines. Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-8 (IL-8) play central roles [5,6]. They drive and sustain the inflammatory cascade, resulting in tissue damage and impaired intestinal barrier function [7].
Current management strategies aim to induce and maintain clinical remission. Biologic agents that target specific inflammatory pathways represent a major advancement [8,9]. Adalimumab, a fully human monoclonal antibody, is one such therapy. It works by binding to and neutralizing TNF-α. This action effectively reduces inflammation and promotes mucosal healing in a significant proportion of patients with moderate-to-severe UC [10,11]. However, clinical experience shows that not all patients achieve an adequate response to anti-TNF therapy [12]. Some experience a loss of response over time, and others face adverse effects. This highlights the need for therapeutic strategies that can improve outcome.
In parallel, traditional Chinese medicine offers complementary approaches. Kangfuxin liquid, derived from Periplaneta americana extract, has been used for various gastrointestinal disorders [13]. Experimental and clinical studies suggest it possesses multiple beneficial properties. These include anti-inflammatory effects, the promotion of tissue regeneration and ulcer repair, and modulation of immune responses [14]. When administered as an enema, Kangfuxin liquid acts directly on the colonic mucosa. This localized delivery may enhance healing at the site of inflammation. This demonstrates the potential of traditional Chinese medicine in treating ulcerative colitis, a notion supported by a meta-analysis comparing a traditional Chinese herbal formula with routine antiulcer drugs [15]. Thus, integrating TCM into UC management may offer additional therapeutic benefit.
The theoretical rationale for combining these two modalities is strong. Adalimumab provides systemic, targeted suppression of a key inflammatory cytokine [16]. Kangfuxin liquid enema may offer local mucosal protection, repair, and additional immunomodulation [17]. Their mechanisms of action are distinct yet potentially synergistic. A combined regimen could therefore address multiple aspects of UC pathophysiology more comprehensively than either agent alone. This approach aligns with the growing interest in integrative treatment models for complex chronic diseases.
Despite the promising rationale, high-quality clinical evidence, particularly from comparative studies with adequate sample sizes, is still scarce. Existing reports on Kangfuxin enema are often limited to small case series or focus on combination with aminosalicylates, leaving its specific additive value when combined with biologics like adalimumab largely unexplored. Therefore, this study aimed to assess clinical effectiveness and safety of Kangfuxin liquid enema combined with adalimumab, compared to adalimumab monotherapy, in patients with ulcerative colitis.
Patients and methods
Research design and cohort selection
This study was carried out strictly adhering to the Declaration of Helsinki and received approval from the Ethics Committee of Shaanxi Provincial Hospital of Traditional Chinese Medicine. All research data were sourced from medical information systems. This study is a retrospective cohort study. Given that this study only utilized existing, de-identified medical records without direct patient contact and posed no additional risks or burdens to patients, the Shaanxi Provincial Hospital of Traditional Chinese Medicine Ethics Committee approved a waiver of the informed consent requirement.
The study population consisted of 240 patients diagnosed with ulcerative colitis and treated at Shaanxi Provincial Hospital of Traditional Chinese Medicine between June 2022 and January 2024. Patients diagnosed with ulcerative colitis according to the diagnostic criteria listed in Diseases of the Colon (Key Points) with complete clinical data required for treatment and age between 18 and 75 years were included. Patients experiencing allergic reactions of any degree post-medication, individuals with cognitive impairment hindering study cooperation, those with severe liver or kidney dysfunction, immune disorders, or other severe digestive system ailments, and patients presenting severe organic lesions, malignant tumors, or malignant diseases were excluded.
Treatments
Based on the actual treatment regimens received during the treatment period, patients were retrospectively divided into a combination therapy group (adalimumab combined with Kangfuxin liquid enema, n = 123) or a monotherapy group (adalimumab alone, n = 117).
The MT group received adalimumab alone (manufactured by Shanghai Henlius Biopharmaceuticals Co., Ltd., approval number: S20200026) by subcutaneous injection. The induction regimen was 160 mg at week 0, 80 mg at week 2, followed by a maintenance regimen of 40 mg every other week. The CT group received the same adalimumab regimen as the MT group, plus Kangfuxin liquid enema. Kangfuxin liquid enema (manufactured by Sichuan Haoyisheng Panxi Pharmaceutical Co., Ltd., approval number: Z51021834) was administered once daily by rectal infusion. Prior to rectal infusion, 50 mL of Kangfuxin liquid enema was diluted with 150 mL of 0.9% sodium chloride solution and heated to 37°C. The infusion was retained in the intestines for at least 30 minutes. Both groups were observed for treatment effects after 8 weeks of therapy. Clinical and assessment data before and after treatment were collected from the patients.
Data collection and outcome measures
Baseline characteristics
Demographic and clinical data including age, gender, disease extent (Montreal classification: E1/E2/E3), disease duration, smoking/alcohol history, past operation history, and prior medication history (aminosalicylates, corticosteroids, immunomodulators) were collected. Patients were classified according to the Montreal Classification, which proposes three subtypes of ulcerative colitis: E1, E2, and E3. E1 refers to ulcerative proctitis, with lesions limited to the rectum and inflammation not extending beyond the rectosigmoid junction. E2 represents left-sided ulcerative colitis (distal UC), with lesions extending beyond the rectosigmoid junction but not reaching the splenic flexure. E3 indicates extensive ulcerative colitis (pancolitis), with lesions extending up to the splenic flexure or involving the entire colon.
Clinical efficacy
Assessed according to a composite criterion integrating symptom improvement and biomarker normalization, and categorized into three levels: Markedly effective: After treatment completion, IL-1, IL-8, TNF-α levels return to normal, mucous bloody stools, diarrhea, and other symptoms completely disappear; Effective: After treatment completion, IL-1, IL-8, TNF-α levels gradually approach normal, mucous bloody stools, diarrhea, and other symptoms significantly improve, and the disease does not worsen; Ineffective: After treatment completion, IL-1, IL-8, TNF-α levels do not change significantly; mucus containing or bloody stools, diarrhea, and other symptoms persist, and the condition gradually worsens. The overall response rate of treatment = (Markedly Effective + Effective) cases/Total cases × 100%.
Endoscopic and histological scoring systems
Mayo score: The Mayo scoring system was utilized, comprising four components, each rated on a scale from 0 to 3. For Stool Frequency, a score of 0 indicates normal frequency, while a score of 3 indicates more than five times daily above baseline. Rectal Bleeding is scored as 0 for no bleeding and 3 for the passage of pure blood. Endoscopic Findings are graded from 0 for normal mucosa to 3 for severe inflammation with spontaneous bleeding. Physician’s Global Assessment ranges from 0 for normal conditions to 3 for severe disease activity. The cumulative score ranges from 0 to 12. Mucosal healing was defined as an endoscopic subscore of 0 or 1 on the Mayo scale. Endoscopic remission was identified by a Mayo endoscopic subscore of 0.
Baron endoscopic score: Mucosal appearance was graded during colonoscopy as: 0 = normal mucosa; 1 = mild inflammation (erythema, decreased vascular pattern); 2 = moderate inflammation (marked erythema, absent vascular pattern, friability, no erosions); 3 = severe inflammation (spontaneous bleeding, ulceration).
Geboes histological score: For histologic remission assessment, colonic biopsy samples obtained during endoscopy were evaluated by two experienced pathologists blinded to the clinical data. The Geboes scoring system was used, which grades architectural changes, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in the epithelium, crypt destruction, and erosions/ulcerations. A score of < 3.0 was defined as histologic remission.
Laboratory and biomarker assays
Fasting peripheral blood samples were collected in the morning at baseline and after 8 weeks of treatment. Serum was separated by centrifugation (3,000 rpm for 15 min) and stored at -80°C until batch analysis.
Inflammatory cytokines: Serum levels of Interleukin-1 beta (IL-1β), Interleukin-8 (IL-8), and Tumor Necrosis Factor-alpha (TNF-α) were quantified using specific commercial sandwich Enzyme-Linked Immunosorbent Assay (ELISA) kits (Human IL-1β/IL-8/TNF-α Quantikine ELISA Kit, R&D Systems, USA). Absorbance was read on a microplate reader (Multiskan GO, Thermo Fisher Scientific, USA).
Oxidative stress markers: Serum Superoxide Dismutase (SOD) activity was measured using the WST-8 method with a commercial kit (SOD Assay Kit-WST, Dojindo Laboratories, Japan). Serum Malondialdehyde (MDA) concentration, reflecting lipid peroxidation, was determined by the thiobarbituric acid reactive substances (TBARS) assay using a commercial kit (MDA Assay Kit, Nanjing Jiancheng Bioengineering Institute, China). Absorbance was measured on a spectrophotometer (UV-1800, Shimadzu Corporation, Japan).
Intestinal barrier function markers: Serum Diamine Oxidase (DAO) activity was measured using a spectrophotometric method based on the oxidation of cadaverine (DAO Activity Assay Kit, Cloud-Clone Corp., China). Serum D-lactate concentration was determined with a specific enzymatic colorimetric assay kit (D-Lactate Colorimetric Assay Kit, Sigma-Aldrich, St. Louis, USA). Analyses were performed on a fully automated biochemical analyzer (AU5800, Beckman Coulter, USA).
Adverse reactions
Adverse reactions, including nausea, constipation, and dizziness, were evaluated with the total incidence rate calculated as follows: (number of cases with nausea + constipation + dizziness)/total cases × 100%.
Quality of life assessment
To comprehensively assess treatment effects, patient quality of life was evaluated using Chinese version of the Inflammatory Bowel Disease Questionnaire-32 (IBDQ-32) [18]. The scale comprises 32 items across four areas: bowel symptoms (10 questions), systemic symptoms (5 questions), emotional function (12 questions), and social function (5 questions). Responses are recorded on a 7-point Likert scale for each item. The cumulative score can range from 32 to 224, with higher scores indicative of a better quality of life.
Statistical analysis
Data were processed using SPSS 25.0 (IBM Corp., Armonk, NY, USA). Normally distributed continuous data were presented as mean ± standard deviation (SD), and independent sample t-tests were utilized for comparisons between groups. Counted data were reported as frequencies (n) and percentages (%), with comparisons conducted using the chi-square test. A two-tailed P value of less than 0.05 was considered significant.
Results
Baseline characteristics
The CT group comprised 123 patients, with 77 males and 46 females, and an average age of 42.73±9.04 years. Disease extent according to the Montreal classification was as follows: E1 in 85 patients (69.11%), E2 in 30 patients (24.39%), and E3 in 8 patients (6.50%). The MT group comprised 117 patients, with 71 males and 46 females, and an average age of 41.82±8.61 years. Disease extent distribution was: E1 in 78 patients (66.67%), E2 in 31 patients (26.50%), and E3 in 8 patients (6.83%). No notable variations were found between the two groups regarding age, gender, disease extent, smoking history, alcohol use, operation history, disease duration, or prior medication history (P > 0.05) (Table 1).
Table 1.
Comparison of baseline data between the CT group and the MT group
| Factor | MT group (n = 117) | CT group (n = 123) | t/χ2 | P |
|---|---|---|---|---|
| Gender, n (%) | 0.093 | 0.760 | ||
| Female | 46 (39.32%) | 46 (37.40%) | ||
| Male | 71 (60.68%) | 77 (62.60%) | ||
| Age | 41.82±8.61 | 42.73±9.04 | 0.796 | 0.427 |
| Disease extent (Montreal), n (%) | 0.167 | 0.920 | ||
| E1 | 78 (66.67%) | 85 (69.11%) | ||
| E2 | 31 (26.50%) | 30 (24.39%) | ||
| E3 | 8 (6.83%) | 8 (6.50%) | ||
| Smoking history, n (%) | 43 (36.75%) | 50 (40.65%) | 0.384 | 0.536 |
| Alcohol use, n (%) | 62 (52.99%) | 60 (48.78%) | 0.425 | 0.514 |
| Operation history, n (%) | 32 (27.35%) | 41 (33.33%) | 1.014 | 0.314 |
| Disease duration (years) | 5.32±1.89 | 5.15±1.76 | 0.745 | 0.457 |
| Medication history, n (%) | ||||
| Aminosalicylic acid | 35 (29.91%) | 40 (32.52%) | 0.190 | 0.663 |
| Corticosteroids | 25 (21.37%) | 30 (24.39%) | 0.310 | 0.578 |
| Immunomodulators | 15 (12.82%) | 14 (11.38%) | 0.117 | 0.733 |
Clinical efficacy comparison
Overall response rate in the CT group (88.62%) significantly exceeded that of the MT group (73.50%) (P = 0.003). In the CT group, treatment in 54.47% of patients was considered markedly effective and in 34.15% it was considered effective, whereas in the MT group, the corresponding proportions were 38.46% and 35.04%, respectively (Table 2).
Table 2.
Comparison of clinical efficacy between the MT group and the CT group after treatment
| Effect Outcome | MT group (n = 117) | CT group (n = 123) | t/χ2 | P |
|---|---|---|---|---|
| Markedly effective, n (%) | 45 (38.46%) | 67 (54.47%) | ||
| Effective, n (%) | 41 (35.04%) | 42 (34.15%) | ||
| Ineffective, n (%) | 31 (26.50%) | 14 (11.38%) | ||
| Overall response rate, n (%) | 86 (73.50%) | 109 (88.62%) | 8.991 | 0.003 |
Mucosal and histologic results comparison
Mucosal healing (Mayo endoscopic subscore 0 or 1) was attained by 56.10% of CT group, whereas it was reached by 32.48% in MT group (P < 0.001). Endoscopic remission (Mayo endoscopic subscore 0) was observed in 65.04% of CT group patients versus 47.01% in the MT group (P = 0.005). Histologic remission (Geboes score < 3.0) was also significantly higher in the CT group (53.66%) than in the MT group (38.46%) (P = 0.018) (Table 3).
Table 3.
Comparison of mucosal and histologic results between the MT group and the CT group after treatment
| Factor | MT group (n = 117) | CT group (n = 123) | t/χ2 | P |
|---|---|---|---|---|
| Mucosal healing, n (%) | 38 (32.48%) | 69 (56.10%) | 13.539 | < 0.001 |
| Endoscopic remission, n (%) | 55 (47.01%) | 80 (65.04%) | 7.923 | 0.005 |
| Histologic remission, n (%) | 45 (38.46%) | 66 (53.66%) | 5.571 | 0.018 |
Mayo score components comparison
Before treatment, there were no significant differences in any Mayo score components between the two groups (P > 0.05). After treatment, all components - stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment - demonstrated markedly better improvement in the CT group relative to the MT group (P < 0.001 for all) (Table 4).
Table 4.
Comparison of Mayo scores between the MT group and CT group after treatment
| Factor | Time | MT group (n = 117) | CT group (n = 123) | t | P |
|---|---|---|---|---|---|
| Stool frequency | Pre-treatment | 2.40±0.40 | 2.44±0.41 | 0.302 | 0.763 |
| Post-treatment | 1.52±0.35 | 1.32±0.31 | 4.560 | < 0.001 | |
| Rectal bleeding | Pre-treatment | 2.34±0.42 | 2.41±0.48 | 1.180 | 0.239 |
| Post-treatment | 1.12±0.31 | 0.95±0.26 | 4.539 | < 0.001 | |
| Endoscopic findings | Pre-treatment | 2.36±0.38 | 2.37±0.37 | 0.049 | 0.961 |
| Post-treatment | 1.65±0.34 | 1.42±0.36 | 4.878 | < 0.001 | |
| Physician’s global assessment | Pre-treatment | 2.36±0.38 | 2.39±0.37 | 0.470 | 0.639 |
| Post-treatment | 1.74±0.35 | 1.57±0.31 | 3.966 | < 0.001 |
Baron endoscopic scores comparison
The Baron endoscopic score did not differ significantly between groups at baseline (P = 0.171). After treatment, the CT group exhibited a significantly lower score (0.86±0.28) compared to the MT group (1.37±0.32) (P < 0.001) (Figure 1).
Figure 1.
Comparison of Baron endoscopic score between MT group and CT group after treatment. ns, no statistically significant difference; ***, P < 0.001.
Inflammatory factor level comparison
Prior to treatment, inflammatory factor levels of IL-1β, IL-8, and TNF-α did not differ notably between the CT group and MT group (P > 0.05). After treatment, all three inflammatory factor levels in the CT group were markedly reduced compared to those in the MT group (P < 0.001) (Table 5).
Table 5.
Comparison of inflammatory factor levels in the MT group and the CT group
| Factor | Time | MT group (n = 117) | CT group (n = 123) | t | P |
|---|---|---|---|---|---|
| IL-1β (pg/mL) | Pre-treatment | 24.35±4.85 | 24.21±4.95 | 0.222 | 0.824 |
| Post-treatment | 10.24±2.38 | 6.67±2.42 | 11.515 | < 0.001 | |
| IL-8 (pg/mL) | Pre-treatment | 282.21±28.23 | 281.95±28.12 | 0.073 | 0.942 |
| Post-treatment | 192.61±18.14 | 160.55±16.73 | 14.245 | < 0.001 | |
| TNF-α (pg/mL) | Pre-treatment | 66.08±6.61 | 65.64±6.56 | 0.523 | 0.602 |
| Post-treatment | 30.60±6.12 | 18.56±3.77 | 18.245 | < 0.001 |
IL-1β: Interleukin-1 beta; IL-8: Interleukin-8; TNF-α: Tumor Necrosis Factor-alpha.
Oxidative stress markers comparison
Baseline levels of SOD and MDA were similar between groups (P > 0.05). After treatment, SOD activity was markedly elevated and MDA concentration was lower in the CT group than the MT group (P < 0.001) (Figure 2).
Figure 2.
Comparison of oxidative stress indicators levels between MT group and CT group. A: SOD (U/mL); B: MDA (nmol/mL); SOD: Superoxide Dismutase; MDA: Malondialdehyde. ns, no statistically significant difference; ***, P < 0.001.
Intestinal barrier function marker comparison
No notable variations were found in DAO activity or D-lactate concentration at baseline (P > 0.05) (Table 6). Post-treatment, both markers were reduced in the CT group compared to the MT group (P < 0.001).
Table 6.
Comparison of intestinal barrier function between the MT group and CT group
| Factor | Time | MT group (n = 117) | CT group (n = 123) | t | P |
|---|---|---|---|---|---|
| DAO (IU/mL) | Pre-treatment | 15.28±3.05 | 15.47±3.11 | 0.461 | 0.645 |
| Post-treatment | 10.52±2.31 | 7.83±2.04 | 9.555 | < 0.001 | |
| D-lactate (μmol/L) | Pre-treatment | 18.45±3.61 | 18.67±3.74 | 0.471 | 0.638 |
| Post-treatment | 12.76±2.65 | 9.53±2.54 | 9.634 | < 0.001 |
DAO: Diamine oxidase.
Adverse reaction incidence rate comparison
Overall incidence of adverse reactions was notably reduced in the CT group (8.94%) than in the MT group (23.94%) (P = 0.002). Individual adverse events (nausea, constipation, dizziness) also showed lower frequencies in the CT group (Table 7).
Table 7.
Comparison of the incidence rate of adverse reactions in the MT group and the CT group
| Factor | MT group (n = 117) | CT group (n = 123) | t/χ2 | P |
|---|---|---|---|---|
| Overall, n (%) | 28 (23.94%) | 11 (8.94%) | 9.898 | 0.002 |
| Nausea, n (%) | 8 (6.84%) | 4 (3.25%) | ||
| Constipation, n (%) | 8 (6.84%) | 2 (1.63%) | ||
| Dizziness, n (%) | 12 (10.26%) | 5 (4.06%) |
Patients’ quality of life comparison
No statistically significant differences were observed in the IBDQ-32 total score or any subscores between the two groups at baseline (P > 0.05 for all). After treatment, the CT group achieved significantly higher scores compared to the MT group across all measures (P < 0.001 for all) (Table 8).
Table 8.
Comparison of IBDQ-32 scores between the MT group and the CT group
| Factor | Time | MT group (n = 117) | CT group (n = 123) | t | P |
|---|---|---|---|---|---|
| IBDQ total score | Pre-treatment | 128.47±21.36 | 127.82±20.18 | 0.240 | 0.810 |
| Post-treatment | 160.75±19.04 | 175.63±17.25 | 6.347 | < 0.001 | |
| Bowel symptoms subscore | Pre-treatment | 31.25±7.12 | 30.88±6.94 | 0.408 | 0.684 |
| Post-treatment | 45.16±6.33 | 52.47±5.87 | 9.285 | < 0.001 | |
| Systemic symptoms subscore | Pre-treatment | 16.84±4.52 | 16.57±4.31 | 0.482 | 0.630 |
| post-treatment | 25.93±2.96 | 29.24±2.11 | 9.922 | < 0.001 | |
| Emotional function subscore | Pre-treatment | 54.12±10.88 | 53.76±10.24 | 0.262 | 0.793 |
| Post-treatment | 68.41±5.07 | 72.15±5.16 | 5.670 | < 0.001 | |
| Social function subscore | Pre-treatment | 27.26±3.23 | 27.05±3.12 | 0.515 | 0.607 |
| Post-treatment | 31.22±1.08 | 32.52±1.14 | 9.034 | < 0.001 |
IBDQ-32: Inflammatory Bowel Disease Questionnaire-32.
Discussion
The findings of this retrospective analysis indicated that the combination of Kangfuxin liquid enema with adalimumab offers a more favorable therapeutic profile for patients with ulcerative colitis compared to adalimumab monotherapy. This integrated approach was associated with superior clinical outcomes across multiple dimensions, including symptom control, endoscopic and histological remission, modulation of systemic inflammation and immune markers, improvement in oxidative stress and intestinal barrier integrity, and a more favorable safety profile.
Firstly, the combination therapy led to a higher overall clinical response rate. A larger percentage of patients in combination group attained both marked and effective outcomes based on composite criteria integrating symptomatic relief and biomarker improvement. This enhanced clinical efficacy suggests a synergistic interaction between the two treatments. Adalimumab exerts its effect by systemically neutralizing TNF-α, a pivotal cytokine in the inflammatory cascade of UC [19]. Kangfuxin liquid, when administered locally by enema, may provide complementary benefits directly at the mucosal level. Its documented properties in promoting tissue regeneration, epithelial repair, and local immunomodulation likely contribute to faster and more complete symptom resolution, explaining the observed clinical advantage over monotherapy [20,21]. This aligns with previous studies suggesting that adjunctive local therapies can improve symptom scores in distal colitis [22].
Secondly, objective assessments of mucosal health strongly favored the combination regimen. Rates of mucosal healing, endoscopic remission, and histologic remission were all higher in the combination group. Endoscopic scores, including both the Mayo endoscopic subscore and the Baron score, showed greater improvement. This indicates that the combination therapy is more effective in reversing the visible and microscopic signs of intestinal inflammation. The rectal administration route used for Kangfuxin liquid in this study is a well-established method for delivering herbal therapies directly to the colonic mucosa. A systematic review of Da-Cheng-Qi decoction, another traditional Chinese herbal formula, demonstrated that rectal administration significantly improved clinical outcomes in patients with intestinal obstruction, with a pooled risk ratio of 1.32 (95% CI 1.24 to 1.39) compared to conservative therapy alone [23]. This supports the rationale that locally delivered herbal therapies can exert direct therapeutic effects on the intestinal mucosa. The pathogenesis of UC involves sustained mucosal injury [24]. While adalimumab effectively suppresses the driving inflammatory signal [25], Kangfuxin’s active components, such as polypeptides and mucopolysaccharides, are known to stimulate epithelial cell proliferation and granulation tissue formation. The direct topical application of Kangfuxin likely accelerates the repair of the damaged epithelial lining, facilitating the structural normalization observed as mucosal and histologic healing [26,27]. This finding is consistent with research demonstrating the wound-healing and mucosa-protective effects of Kangfuxin in other gastrointestinal ulcer models [28].
Thirdly, combination therapy led to a more substantial reduction in systemic inflammatory burden. Post-treatment serum levels of key pro-inflammatory cytokines, namely IL-1β, IL-8, and TNF-α, were reduced in the combination group compared to the monotherapy group. This suggests that the local anti-inflammatory and immunomodulatory actions of Kangfuxin enema contribute to a broader systemic dampening of inflammation [29]. Chronic inflammation in UC is fueled by a network of cytokines. Adalimumab targets TNF-α specifically, but other pathways may remain active [30]. Kangfuxin has been shown in experimental studies to inhibit pathways like NF-κB, which regulates the expression of multiple cytokines, including IL-1β and IL-8 [31]. Therefore, the combination may disrupt the inflammatory network at more than one node, leading to a more comprehensive suppression of cytokine production, as reflected by the biomarker levels.
Furthermore, the combination therapy demonstrated a positive impact on oxidative stress markers and markers of intestinal barrier function. The activity of the antioxidant enzyme SOD was higher, while the level of the lipid peroxidation product MDA was lower in the combination group. Oxidative stress is a critical mediator of tissue damage in UC. The improvement in these markers suggests that the combination regimen better ameliorates the redox imbalance in the intestinal environment. This may be attributed to the known antioxidant properties of Kangfuxin liquid, which may complement the anti-inflammatory action of adalimumab to reduce overall oxidative insult [25,32]. Concurrently, serum levels of DAO and D-lactate, which inversely correlate with intestinal mucosal integrity, were lower in the combination group. This indicates better preservation or restoration of the intestinal epithelial barrier. A leaky gut barrier allows bacterial translocation and perpetuates inflammation. By promoting mucosal healing and reducing inflammation, the combination therapy appears more effective in restoring this critical physical and functional barrier, which is a key therapeutic goal in UC management [33,34].
An important practical finding is the lower overall occurrence of adverse reactions in combination group. This suggests that integrative approach may not only be more efficacious but also well-tolerated. The localized action of Kangfuxin enema may allow for a synergistic therapeutic effect without amplifying systemic side effects commonly associated with biologic therapies. Alternatively, by potentially enhancing mucosal healing and reducing overall disease activity, the combination might mitigate some gastrointestinal discomfort. This improved safety profile is a significant consideration for long-term treatment strategies in a chronic condition like UC [16,35,36].
Finally, this combination therapy led to a superior improvement in patient-reported quality of life. The significant and consistent gains across all domains of the IBDQ-32 in the combination group - ranging from core bowel symptoms to emotional and social function - provide direct evidence that the clinical and endoscopic benefits translate into meaningful gains from the patient’s perspective. This holistic improvement underscores the value of an integrative approach that not only targets mucosal healing but also addresses the broader well-being of patients living with a chronic disease like UC. The correlation between enhanced objective outcomes (mucosal healing, reduced inflammation) and superior subjective quality of life further strengthens the rationale for this combined regimen.
The observed benefits of this combination find support in the growing body of literature on integrative gastroenterology. While adalimumab is a cornerstone biologic therapy with well-established efficacy, research continues to seek strategies to improve response rates and durability [37]. Studies on other locally acting agents, like mesalamine enema, combined with systemic biologics have shown promise. Our findings extend this concept to a traditional herbal extract with documented reparative properties. The mechanisms - systemic cytokine blockade paired with local mucosal protection, repair, and broad-spectrum immunomodulation - provide a plausible framework for the superior outcomes [38].
Limitations
Several limitations are acknowledged in this study. The retrospective design introduced inherent risks of selection bias and unmeasured confounders, despite balanced baseline characteristics. The sample size, while larger than many preliminary reports, may still limit the generalizability of the findings. The single-center nature of the study means the results may have been influenced by local patient demographics and treatment protocols. The follow-up period was focused on short-term outcomes at 8 weeks; therefore, the long-term durability of the combined effect on clinical remission, quality of life, maintenance of remission, and impact on hospitalization or surgery rates requires investigation. Additionally, the specific immunological and molecular mechanisms underlying the observed synergy were not explored in depth and warrant further basic research.
Future prospective, randomized controlled trials with larger, multi-center cohorts and longer follow-up durations are essential to confirm these findings and evaluate the sustained benefits. Such studies should employ standardized outcome measures and consider exploring predictive biomarkers to identify patients most likely to benefit from this combination strategy. Investigations into the optimal dosing and duration of the Kangfuxin enema component within the combined regimen would also be valuable for clinical practice.
Conclusion
A combination of Kangfuxin liquid enema and adalimumab demonstrated a more comprehensive therapeutic effect in ulcerative colitis than adalimumab alone. This regimen was associated with enhanced clinical and endoscopic remission, greater suppression of systemic inflammation, improved oxidative stress and gut barrier markers, and a reduced burden of adverse events. These results support the potential of this integrative treatment model as a strategy for managing ulcerative colitis, meriting further rigorous clinical evaluation.
Acknowledgements
This study was supported by the Shaanxi Provincial Administration of Traditional Chinese Medicine (No. SXZYLP-2024005).
Disclosure of conflict of interest
None.
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