Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis | Scientific Reports – Nature.com

Study design and patient population

A single-center retrospective study design was used to investigate the follow-up of patients treated with IN between 2015 and 2020. Powdered IN (Fujian Province, China) was purchased from Uchidawakanyaku Ltd. (Tokyo, Japan).

Patients on treatment with IN (0.5 or 1.0g per day) and those who exhibited clinical response after 8weeks of IN therapy were enrolled in this study. The IN dose was determined after a consultation with each patient (one patient used 0.5g IN per day, other patients used 1.0g IN per day). Patients treated with Chinese herbal medicines, including IN, in private clinics were excluded. Informed consent was obtained from all subjects.

We set the primary endpoint as the cumulative relapse rate of UC in patients after IN discontinuation at 52weeks, who once achieved clinical response with IN treatment; the secondary endpoint was set as the cumulative relapse rate in patients with UC after IN discontinuation at 8 and 26weeks.

Clinical data, such as symptoms, blood investigations, and medication use, were obtained from the medical records of the Keio University Hospital. Blood investigations included white blood cell count and hemoglobin, hematocrit, serum total protein, albumin, total bilirubin, total cholesterol, aspartate aminotransferase(AST), alaneine aminotransferase(ALT), alkaline phosphatase, gamma-glutamyl trans peptide(GGT), amylase, urea nitrogen, creatinine, glucose, and C-reactive protein (CRP) levels. All patients (>18years) were diagnosed with UC based on the Japanese UC criteria. Disease duration was defined as the period between the diagnosis of UC and initiation of IN treatment. The clinical severity of UC was determined based on the partial Mayo (pMayo) score. The follow-up period was defined as the duration from IN initiation to the last visit. All patients in this study had moderate to severe disease (pMayo Score 59 before the start of IN). Clinical response was defined as a decrease in pMayo score1 or a decrease of3 from the baseline24. The duration of IN treatment depends on the patients condition. When side effects were reported, we recommended the patients to discontinue IN. Clinical relapse was defined as the addition of a new therapeutic agent or an increase in pMayo score of3.

To predict the markers for patients who sustained remission 52weeks after IN discontinuation, we divided them into two groups: the short remission group, which included patients who relapsed within 52weeks after IN discontinuation, and the long remission group, which included patients who sustained remission 52weeks after IN discontinuation. We analyzed the predictive markers for patients who sustained remission 52weeks after IN discontinuation using medical history and laboratory data.

Cumulative relapse rates after IN discontinuation were estimated using the KaplanMeier method (GehanBreslowWilcoxon test). Statistical significance was set at P<0.05. Risk factor is evaluated using univariate analysis (chi-square and t- tests for independent samples) and multivariate analysis performed between the previously described groups divided by duration of IN therapy or patients relapse within 52weeks after IN discontinuation.

This study was approved by the Ethical Review Board of Keio Hospital (20211003) and was conducted in accordance with the Declaration of Helsinki principles.

Among the patients with UC who received IN treatment at our hospital between 2015 and 2020, 111 patients whose progress from the initiation of IN was traceable were included (Fig.1). Of these, 39 patients were excluded from the study with the following reasons: treatment ineffectiveness (n=19), intolerance (n=14), UC relapse while using IN (n=2), present use of IN (n=2), requirement of surgery (n=1), and transfer to a different hospital (n=1). Remaining 72 patients achieved clinical response 8weeks after IN treatment, whose chatracteristics were analyzed in this study. All 72 patients undertook IN for at least 8weeks. Some patients showed a slightly elevated level of liver transaminases but liver transaminase levels were not so high (AST, ALT<45) during the IN treatment.

The mean age at diagnosis (meanstandard deviation [SD]) was 28.113.9years; the malefemale ratio was 5050. The disease duration (meanSD) was 8.287.5years; 58.3% (n=42), 37.5% (n=27), and 2.8% (n=2) of patients had extensive UC, left-sided UC, and proctitis, respectively. The pMayo scores were 6 and 1 at initiation of IN and 8weeks after IN initiation, respectively (Table 1). We defined the past treatment history of the patients who had used other drugs 8weeks before IN initiation and concomitant treatment of the patients who used drugs within 8weeks before IN initiation and during IN intake.

Regarding treatment history, all patients received 5-ASA and 72.9% (n=51), 50% (n=36), 40.3% (n=29), 4.17% (n=3), 23.6% (n=17), 8.33% (n=6), and 23.6% (n=17) received corticosteroids (prednisolone: PSL), immunomodulators (IM), anti-TNF- inhibitors, anti-47 integrin inhibitors, calcineurin inhibitors, JAK inhibitors, and cytapheresis, respectively. We also analyzed concomitant therapy administered eight weeks before and during IN intake. In total, 90.3% (n=65) of the patients received 5-ASA during IN treatment. All 30 patients used IM at 8weeks of IN and maintained these medications during the course of IN treatment. Six patients received anti-TNF therapy 8weeks prior to IN initiation, and six discontinued treatment at the time of IN discontinuation. Calcineurin and JAK inhibitors were used in six and two patients, respectively, 8weeks prior to the start of IN and all stopped by the time of IN discontinuation. One patient underwent cytapheresis 8weeks prior to the IN initiation and stopped before the IN discontinuation. Another patient used anti-47 integrin inhibitor 8weeks prior to the start of IN and is still using it. Sixteen patients used PSL 8weeks prior to IN start, 11 patients stopped them at the time of IN start, and the remaining used corticosteroids, but half lower than 20mg per day and all patients stopped them at the time of IN discontinuation. To determine whether concomitant medications affected the severity of the cases before IN intake and at the time of IN discontinuation, we analyzed the pMayo score according to concomitant medication (Fig.2). We did not observe any differences in disease activity between concomitant medications before IN intake and at the time of IN discontinuation.

The pMayo score was determined based on concomitant therapy before IN intake and at the time of IN discontinuation (n=72). Bar graph is shown in average score of pMayo before IN intake (A) and at the time of IN discontinuation (B). (Bar graph represents mean+sem, X axis, 5ASA: patients take 5ASA only before IN intake, 5ASA/IM: patients take 5ASA plus IN before IN intake, PSL: patients take 5ASA plus PSL before IN intake, Bio: patients take 5ASA plus biologics (anti-TNF inhibitor, anti-47 integrin inhibitor, JAK inhibitor) before IN intake, Cal: patients take 5ASA plus calcinurin inhibitor before IN intake) IN indigo naturalis.

Blood investigations were compared before and after discontinuation of IN. At the time of IN discontinuation, hemoglobin levels tended to increase, albumin levels significantly increased, and leukocyte, CRP, and platelet levels significantly decreased (Table 2). We did not find severe AEs such as PAH and intestinal intussusception in this study participants.

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Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis | Scientific Reports - Nature.com