Efficacy and safety of filgotinib as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a post-hoc analysis of the phase 2b/3 SELECTION trial

Background/Aims@#The safety and efficacy of filgotinib, a once-daily oral Janus kinase 1 preferential inhibitor, were evaluated in Japanese patients with ulcerative colitis (UC) in the phase 2b/3 SELECTION trial. @*Methods@#SELECTION (NCT02914522) was a randomized, placebo-controlled trial comprising 2 induction studies and a maintenance study. Adults with moderately to severely active UC were randomized in induction study A (biologic-naïve) or B (biologic-experienced) to receive filgotinib 200 mg, 100 mg, or placebo once daily for 11 weeks. Patients in clinical remission or Mayo Clinic score response at week 10 entered the 47-week maintenance study. Efficacy and safety outcomes were assessed in Japanese patients enrolled in Japan. @*Results@#Overall, 37 and 72 Japanese patients were enrolled in Japan in induction studies A and B, respectively, and 54 entered the maintenance study. Numerically higher proportions of filgotinib 200 mg-treated than placebo-treated patients achieved clinical remission in induction study A (4/15 [26.7%] vs. 0/6 [0%]) and the maintenance study (5/20 [25.0%] vs. 0/9 [0%]), but not induction study B (1/29 [3.4%] vs. 1/14 [7.1%]). Both doses were well tolerated, and no new safety signals were noted. Herpes zoster was reported in 1 filgotinib 200 mg-treated patient in each of induction study A (2.3%, 1/44) and the maintenance study (5.0%, 1/20). @*Conclusions@#These data, alongside those of the overall SELECTION population, suggest the potential of filgotinib 200 mg as a viable treatment option for Japanese patients with UC. Owing to small patient numbers, data should be interpreted cautiously.

Two Cases with Different Symptoms Treated with Saikokaryukotsuboreito : A Girl in Her Early Teens Who was Unable to Attend School and Her Grandmother with Increased Fatigability / 日本東洋医学雑誌

Kampo formulations can be prescribed for patients with different symptoms. We report two cases with different symptoms : a girl in her early teens and her grandmother. Case 1 was a 13-year-old girl and the grandchild of Case 2. She was unable to attend school. Case 2 was a 73-year-old woman who presented with increased fatigability. After treatment with saikokaryukotsuboreito, both cases experienced improved symptoms. It was suggested that they had the same Kamp pathology because they were related by blood and shared a common environment. Consequently, both cases were effectively treated using one formulation : saikokaryukotsuboreito.

The Feature of Patients Treated with Daiobotampito, Especially About Urination, Before and During the Song Dynasty / 日本東洋医学雑誌

It is written about daiobotampito in ‘Jin Gui Yao Lue' that the patients who should be treated with the for­mula urinated smoothly. On the other hand, Kampo doctors today tend to use daiobotampito for difficulty of urination. We investigated the feature of daiobotampito in old medical textbooks, especially about “urination,” “gonorrhea,” and “intestinal abscess.” We searched old medical textbooks for daiobotampito, which were writ­ten or published before or during the Song Dynasty. In the textbooks other than ‘Jin Gui Yao Lue,' it is written that the patients urinated frequently. In the textbooks other than ‘Jin Gui Yao Lue' and ‘Ishimpo,' it is written that the patients sometimes urinated difficultly. In the old medical textbooks before or during the Song Dynasty, urination of the patients who should be treated with daiobotampito was smooth but sometimes difficult.

Clinical management for small bowel of Crohn’s disease in the treat-to-target era: now is the time to optimize treatment based on the dominant lesion

A treat-to-target strategy, in which treatment is continuously adjusted according to the results of scheduled objective monitoring, is optimal for patients with Crohn’s disease (CD) in the era of biologics. The small bowel is a common site of intractable CD, which may result from multiple strictures or expanding lesions. To improve the prognosis of patients with small bowel CD, lesions should be proactively monitored within the subclinical phase. Objective assessment of small bowel lesions is technically difficult, however, due to the relatively poor correlation between endoscopic activity and clinical symptoms or biomarker titers. The presence of proximal small bowel lesions and asymptomatic “Real Silent CD” must be considered. Endoscopy remains the gold standard to assess these lesions. In clinical practice, the advantages and disadvantages of each imaging modality and biomarker must be carefully weighed for appropriate application and reliable monitoring. The prevalence of small bowel lesions depends on the precision of the imaging modality used for detection. Clinical management should be based on the dominant location of the intestinal lesions rather than classical classification. Optimal strategies for detecting and treating small bowel lesions in patients with CD must be developed utilizing reliable, precise, and objective monitoring.

Prediction Model for Deficiency-Excess Patterns, Including Medium Pattern / 日本東洋医学雑誌

We have previously reported on a predictive model for deficiency-excess pattern diagnosis that was unable to predict the medium pattern. In this study, we aimed to develop predictive models for deficiency, medium,and excess pattern diagnosis, and to confirm whether cutoff values for diagnosis differed between the clinics. We collected data from patients' first visit to one of six Kampo clinics in Japan from January 2012 to February 2015. Exclusion criteria included unwillingness to participate in the study, missing data, duplicate data, under 20 years old, 20 or less subjective symptoms, and irrelevant patterns. In total, 1,068 participants were included. Participants were surveyed using a 153-item questionnaire. We constructed a predictive model for deficiency, medium, and excess pattern diagnosis using a random forest algorithm from training data, and extracted the most important items. We calculated predictive values for each participant by applying their data to the predictive model, and created receiver operating characteristic (ROC) curves with excess-medium and medium-deficiency patterns. Furthermore, we calculated the cutoff value for these patterns in each clinic using ROC curves, and compared them. Body mass index and blood pressure were the most important items. In all clinics, the cutoff values for diagnosis of excess-medium and medium-deficiency patterns was > 0.5 and < 0.5, respectively. We created a predictive model for deficiency, medium, and excess pattern diagnosis from the data of six Kampo clinics in Japan. The cutoff values for these patterns fell within a narrow range in the six clinics.

Two Elderly Cases of Constipation with Irritability Diagnosed as Alzheimer's Dementia after Successfully Treated with Daijokito / 日本東洋医学雑誌

We report two cases of irritable bowel syndrome (IBS) with predominant constipation successfully treated with daijokito and then diagnosed as Alzheimer's dementia. [Case 1] An 82-year-old man. He had been treated for IBS with probiotic and purgative. However, the symptom of IBS did not get cured and he had suffered from digestive symptom with iracund mental condition. [Case 2] A 74-year-old man. He suffered from abdominal pain and constipation so he needed enema and stool extraction frequently. He sometimes angered if he could not get treatment without delay. In both cases, their bowel and mental condition improved after treatment with daijokito. After their conditions improved, we checked their cognitive function, and found the levels of their cognitive function were low. We diagnosed them as Alzheimer's dementia. The patients probably had felt the difficulty and gotten mental stress on usual days because of dementia, so the mental stress could complicate the symptoms of IBS. Daijokito probably improved the digestive symptom due to IBS and the mental stress from dementia of these patients, and after the treatment we could diagnose the dementia. Elderly patients with constipation and iracund mental condition might have dementia.

Usefulness of fecal calprotectin by monoclonal antibody testing in adult Japanese with inflammatory bowel diseases: a prospective multicenter study

BACKGROUND/AIMS: Noninvasive objective monitoring is advantageous for optimizing treatment strategies in patients inflammatory bowel disease (IBD). Fecal calprotectin (FCP) is superior to traditional biomarkers in terms of assessing the activity in patients with IBD. However, there are the differences among several FCP assays in the dynamics of FCP. In this prospective multicenter trial, we investigated the usefulness of FCP measurements in adult Japanese patients with IBD by reliable enzyme immunoassay using a monoclonal antibody. METHODS: We assessed the relationship between FCP levels and disease or endoscopic activity in patients with ulcerative colitis (UC, n=64) or Crohn’s disease (CD, n=46) compared with healthy controls (HCs, n=64). RESULTS: FCP levels in UC patients strongly correlated with the Disease Activity Index (rs =0.676, P < 0.0001) and Mayo endoscopic subscore (MES; rs =0.677, P < 0.0001). FCP levels were significantly higher even in patients with inactive UC or CD compared with HCs (P=0.0068, P < 0.0001). The optimal cutoff value between MES 1 and 2 exhibited higher sensitivity (94.1%). FCP levels were significantly higher in active UC patients than in inactive patients (P < 0.001), except those with proctitis. The Crohn’s Disease Activity Index tended to correlate with the FCP level (rs =0.283, P=0.0565). CONCLUSIONS: Our testing method using a monoclonal antibody for FCP was well-validated and differentiated IBD patients from HCs. FCP may be a useful biomarker for objective assessment of disease activity in adult Japanese IBD patients, especially those with UC.

Effect of elemental diet combined with infliximab dose escalation in patients with Crohn's disease with loss of response to infliximab: CERISIER trial

No abstract available.

A Case of Generalized Anxiety Disorder for Three Years After the Postpartum Period Treated with Kyukichoketsuin / 日本東洋医学雑誌

We report a case of a 39-year-old female who suffered from generalized anxiety disorder for 3 years after a spontaneous abortion and was successfully treated with kyukichoketsuin. She got generalized anxiety disorder and had difficulty to stay in a crowd after she had a spontaneous abortion at the age of 36. She visited our Kampo clinic because of the anxiety at her age of 39. We prescribed her yokukansankachimpihange for 6 months, but she still suffered from anxiety. After we changed yokukansankachimpihange to kyukichoketsuin, her anxiety improved. Kyukichoketsuin is a formula for various kinds of bad conditions during the postpartum period, which was described as the first therapeutic agent in “Manbyokaishun.” In this case, although the patient had suffered from mental disorder for three years after a spontaneous abortion, she showed a favorable response to kyukichoketsuin treatment. This result suggests that kyukichoketsuin may be effective for years of mental problems after parturition.

Predicting outcomes to optimize disease management in inflammatory bowel disease in Japan: their differences and similarities to Western countries

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract, with increasing prevalence worldwide. IBD Ahead is an international educational program that aims to explore questions commonly raised by clinicians about various areas of IBD care and to consolidate available published evidence and expert opinion into a consensus for the optimization of IBD management. Given differences in the epidemiology, clinical and genetic characteristics, management, and prognosis of IBD between patients in Japan and the rest of the world, this statement was formulated as the result of literature reviews and discussions among Japanese experts as part of the IBD Ahead program to consolidate statements of factors for disease prognosis in IBD. Evidence levels were assigned to summary statements in the following categories: disease progression in CD and UC; surgery, hospitalization, intestinal failure, and permanent stoma in CD; acute severe UC; colectomy in UC; and colorectal carcinoma and dysplasia in IBD. The goal is that this statement can aid in the optimization of the treatment strategy for Japanese patients with IBD and help identify high-risk patients that require early intervention, to provide a better long-term prognosis in these patients.

Problem Extraction of Browser-Based Questionnaire System and its Solution for a Patient-Centered System / 日本東洋医学雑誌

We have developed and operated a browser-based questionnaire system for Kampo medicine based on conventional questionnaires and review of systems to reveal implicit Kampo wisdom both in patients' questionnaire data and in some Kampo specialists' examination data. However, the questionnaire data were found to be inaccurate because too many questions were included and cumbersome input steps were required. The purpose of the present study was to solve these problems and to develop a new patient-centered questionnaire system with fewer questions and an easier input method. After analyzing inquiry database from collaborating institutes and hospitals, we deleted, combined, and added questions. We changed the evaluation method of symptoms from a visual analogue scale to a simple staged evaluation, and introduced another method to evaluate the main symptoms in each time of visit using a visual analogue scale. At the same time, a tool for predicting Kampo pattern diagnoses based on the questionnaire data was implemented. We have already started collecting more accurate and reliable data using the new questionnaire system. It is expected to support routine practices and facilitate more precise clinical research on Kampo medicine.

Two Cases of Chest Symptoms that Their Physical Strength got Better After Treatment with Tokito / 日本東洋医学雑誌

Tokito is a Kampo formulation for treating chest and/or abdominal pain symptoms of individuals with deficiency pattern and cold pattern. Here, we report cases of chest symptoms except pain. Case 1 was an 81-year-old man who presented with chest tightness, and Case 2 was a 77-year-old man who presented with palpitation. Their symptoms improved remarkably and their physical strength got better after treatment with tokito. Tokito comprises ginseng and astragalus root, the same as the one used in hochuekkito, which is a well-known qi-tonifying formulation. It is suggested that tokito is effective as qi-tonifying formulation for a variety of chest symptoms in patients with deficiency pattern and cold pattern.

Inclusion of Ginseng in Kanzoshashinto / 日本東洋医学雑誌

Kanzoshashinto consists of seven medicinal herbs including ginseng. The formula for kanzoshashinto in the Chinese medical text “Jinguiyaolue” consists of the seven herbs, but its formula in “Shanghanglun,” a second medical reference, lists only six herbs and does not include ginseng. We investigated if formulas for kanzoshashinto in traditional Chinese and Japanese medical books included ginseng. We searched modern Japanese databases using the terms kanzoshashinto and ginseng. We also searched medical books written during the Song Dynasty in China and the Edo period in Japan. We found one article in a modern Japanese database that discusses kanzoshashinto and ginseng. The article stated that kanzoshashinto formula included ginseng only described in the Song medical text Jinguiyaolue. Kanzoshashinto formula in other ancient Chinese medical references did not list ginseng as one of the components of the medicine. This research confirmed the statements written in ancient Chinese medical references : doctors could add ginseng to kanzoshashinto. During the Edo period in Japan, most doctors prescribed a kanzoshashinto formulation that included ginseng. In the medical reference “Jinguiyaolue,” kanzoshashinto with ginseng is described as a treatment for kowaku, an unstable psychological state. In the medical reference “Shanghanglun,” kanzoshashinto without ginseng was used to treat severe diarrhea. Therefore, it is possible that kanzoshashinto without ginseng might be a more effective treatment for diarrhea. Further studies are required to examine the efficacy of kanzoshashinto without ginseng in treating severe diarrhea.

<b>A Case of Involuntary Movements Treated with Yokukansankashakuyakukoboku</b> / 日本東洋医学雑誌

We report the case of a 17-year-old male who had involuntary movements treated with yokukansankashakuyakukoboku. He had first recognized the involuntary movement 6 years previously. His symptom could not be alleviated with neurological and psychological treatments, and he visited our clinic for treatment with Kampo medicine. His symptom gradually alleviated with yokukansankashakuyakukoboku. The ancient physician Sekki (薛已) created yokukansan in China's Ming Dynasty. Yokukansan and its various add-on combinations were used in the Edo Era of Japan. Keisetsu Ohtsuka then created yokukansankashakuyakukoboku, which is however now rarely used because there is no extract drug in Japan. There are markedly nervous patients however, who can be treated with this formula. Thus, the authors feel that more research needs to be done on the differences between yokukansan and yokukansankashakuyakukoboku.

<b>Pain from Right Lateral Epicondylitis Successfully Treated with Uyakujunkisan : A Case Report</b> / 日本東洋医学雑誌

Typically, Japanese Kampo doctors use formulas classified for treating blood stasis, to treat pain. However,there have been few reported cases where pain was treated with formulas classified for treating qi stagnation. Here, we report a case of right lateral epicondylitis in a 48-year-old woman who was treated with a focus on qi stagnation and with uyakujunkisan. She underwent conservative treatment at an orthopedic clinic for ten months, but her pain was not relieved. Hence, she opted for Kampo treatment. She was in a state of melancholy, felt heaviness throughout her body, and had irregular menstruation. These symptoms were mainly related to qi stagnation, and hence, we chose uyakujunkisan without white silkworm, but with aconite root. One month later, the stiffness in her shoulder improved and the pain was reduced. Magnetic resonance imaging taken 2 months later showed an improvement in the lesion. Nine months later, her menstruation became regular, and 11 months later, the pain had almost completely resolved and she could comfortably perform activities of daily living. Uyakujunkisan is introduced in the classical textbooks, and we interpret uyakujunkisan as a formula that can treat pain with qi stagnation. In Kampo treatment, effective pain treatment involves consideration of not only local blood stasis but also general qi stagnation.

<b>A Case of Fever and Fatigability Treated with Hangeshashinto</b> / 日本東洋医学雑誌

It is not a few cases that present with fever and fatigability of an unknown cause. We report a case of fever and fatigability treated effectively with hangeshashinto. The case was 47 year-old woman who had been having fever and fatigability for three years. Sometimes she could not go to work because of this malaise. She was diagnosed with patterns of qi deficiency, upper body heat and lower body cold, qi stagnation and stagnant blood. We carefully considered shinkahiko (epigastric tightness and resistance).<br>Hangeshashinto was prescribed, and her complaints improved remarkably. Hangeshashinto is a well-known Kampo formulation for treating disorders of digestion. But this suggested that hangeshasinto is effective for a variety of symptoms in patients with digestional disorders, who also have a shinkahiko condition.

<b>A Case of Depression Effectively Treated with B</b><b>ofutsushosan</b> / 日本東洋医学雑誌

Bofutsushosan has recently become a well-known Kampo formulation for treating metabolic syndrome. It is effective for obesity in people who have mental disorder, but few reports suggest that it is effective for mental disorder itself. We report a case of depressive complaints treated effectively with bofutsushosan. The case was 63 years-old male who had had depression for twenty years. His depressed condition had been stable owing to antidepressant therapies. However, he had could not read books, and so had not been able to enjoy the pleasure of reading since nine months previously. He did not believe that his depression had taken a turn for the worse, but rather that he had the partial androgen decline (or deficiency) of aging males. Therefore he did not consult his psychiatrist, and he wanted to be treated with Kampo formulations. He was diagnosed with a hyperfunctional constitution, heat pattern, and a <i>ki </i>obstruction pattern. Bofutsushosan was prescribed, and his complaints improved remarkably. This suggests that bofutsushosan is effective for treatment of not only obesity but also mental disorder itself.

Changes in susceptibility to antibacterial agents of <i>Haemophilus influenzae</i> isolated in central Tokyo for 10 years (2004-2013) / 日本プライマリ・ケア連合学会誌

<b>Introduction</b> : The purpose of this study was to clarify the antimicrobial susceptibility of <i>Haemophilus influenzae</i> in central Tokyo over a ten-year period.<br><b>Methods</b> : We investigated the susceptibility of <i>Haemophilus influenzae</i> isolated in Tokyo Saiseikai Central Hospital for 10 years from 2004 through 2013.<br><b>Results</b> : Significant increases in the proportion of strains resistant to ampicillin, ampicillin / sulbactam and cefditoren pivoxil were noted for some years in comparison to the first year studied. There were no significant changes in the susceptibility to levofloxacin and clarithromycin. The proportion of strains resistant to ampicillin and cefditoren pivoxil showed statistically significant increases during the study period. The proportion of the strains resistant to ampicillin / sulbactam isolated from children was greater than from adults for every year studied. Levofloxacin resistant strains were isolated only from adults. The proportion of strains resistant to clarithromycin were about 1% in Japanese national surveillance data, but the proportions in this study were over 9%.<br><b>Conclusion</b> : Over a ten-year period in central Tokyo, <i>Haemophilus influenzae</i> strains resistant to ampicillin and cefditoren pivoxil increased. Strains resistant to clarithromycin occurred at a higher rate than nationally.

<b>Current Status of Kampo Medicine Learning by Japanese Physicians for Cancer Treatment </b> / 日本東洋医学雑誌

The aim of the current nationwide survey was to investigate the Kampo medicine experiences of Japanese physicians working at hospitals designated as core cancer centers by the Ministry of Health, Labour and Welfare. Among the 900 physicians surveyed, 92.4% reported having prescribed Kampo medications, of whom 73.5% reported having prescribed them for cancer patients. Despite this high percentage, only 28.7% of the physicians had studied Kampo medicine.<br>This survey found that over 40% of physicians in each generation had no intention of learning Kampo medicine. When asked to categorize their expectation of Kampo efficacy, about 30% said they had an ‘expectation’, a ‘no and yes expectation’, and ‘no expectation’ respectively.<br>However, physicians who had experience learning Kampo medicine had more expectation than physicians who had not. And the same expectation tendency for prophylaxis treatment was shown in physicians with that experience and those without. This difference is disadvantageous to patients. We therefore believe it necessary to create an environment in which physicians can learn Kampo medicine and methodology, which engenders cooperation between Kampo specialists and Japanese physicians in the treatment of cancer.

<b>A Case of Intractable Vomiting After Distal Gastrectomy Treated with Bakumondoto</b> / 日本東洋医学雑誌

There have been few reports on an antiemetic effect of bakumondoto. An 84 year old man was referred to the department of internal medicine for Kampo treatment of intractable vomiting since having a gastrectomy 6 years previously. He had experienced persistent regurgitation of gastric fluids at dawn and antiemetic and antiacid drugs were of little help. He had had a gastrojejunostomy 4 years previously for an intestinal obstruction. After the gastrojejunostomy, vomiting persisted despite of the administration of antiacids, rikkunshito or daikenchuto. Physical examination revealed only slight edema of the legs. An upper gastrointestinal series, blood tests and head CT scan revealed no specific vomiting cause. After referral to our department, we tried hangeshashinto, and shinbuto in vain. Then we prescribed bakumondoto. He reported that the frequency of his vomiting reduced in 3 weeks, and that the vomiting disappeared in 2 more weeks. Thus we consider that not only cough but also vomiting can be treated with bakumondoto.