Efficacy of cytapheresis in patients with ulcerative colitis showing insufficient or lost response to biologic therapy.

For the optimal management of refractory ulcerative colitis (UC), secondary loss of response (LOR) and primary non-response to biologics is a critical issue. This article aimed to summarize the current literature on the use of cytapheresis (CAP) in patients with UC showing a poor response or LOR to biologics and discuss its advantages and limitations. Further, we summarized the efficacy of CAP in patients with UC showing insufficient response to thiopurines or immunomodulators (IM). Eight studies evaluated the efficacy of CAP in patients with UC with inadequate responses to thiopurines or IM. There were no significant differences in the rate of remission and steroid-free remission between patients exposed or not exposed to thiopurines or IM. Three studies evaluated the efficacy of CAP in patients with UC showing an insufficient response to biologic therapies. Mean remission rates of biologics exposed or unexposed patients were 29.4 % and 44.2%, respectively. Fourteen studies evaluated the efficacy of CAP in combination with biologics in patients with inflammatory bowel disease showing a poor response or LOR to biologics. The rates of remission/response and steroid-free remission in patients with UC ranged 32%-69% (mean: 48.0%, median: 42.9%) and 9%-75% (mean: 40.7%, median: 38%), respectively. CAP had the same effectiveness for remission induction with or without prior failure on thiopurines or IM but showed little benefit in patients with UC refractory to biologics. Although heterogeneity existed in the efficacy of the combination therapy with CAP and biologics, these combination therapies induced clinical remission/response and steroid-free remission in more than 40% of patients with UC refractory to biologics on average. Given the excellent safety profile of CAP, this combination therapy can be an alternative therapeutic strategy for UC refractory to biologics. Extensive prospective studies are needed to understand the efficacy of combination therapy with CAP and biologics.

A nationwide survey concerning the mortality and risk of progressing severity due to arterial and venous thromboembolism in inflammatory bowel disease in Japan.

BACKGROUND: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. AIMS: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. METHODS: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. RESULTS: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. CONCLUSION: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed.

Cytapheresis re-induces high-rate steroid-free remission in patients with steroid-dependent and steroid-refractory ulcerative colitis.

BACKGROUND: It is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients. AIM: To clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients. METHODS: We retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger's clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test. RESULTS: The rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger's clinical activity index scores were significantly decreased after CAP (P < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period. CONCLUSION: Our results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.

Factors associated with the outcomes in ulcerative colitis patients undergoing granulocyte and monocyte adsorptive apheresis as remission induction therapy: A multicenter cohort study.

Ulcerative colitis (UC) patients harbor activated myeloid leukocytes, which exacerbate and perpetuate UC by releasing inflammatory cytokines. Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn depletes elevated myeloid leukocytes, inducing efficacy with favorable safety. To understand how the clinical outcome with GMA is affected by prior corticosteroid treatment or concomitant immunomodulators, a retrospective multicenter study in 102 UC patients, who had not responded well to first-line medications was undertaken. The remission rates after a course of GMA therapy were significantly higher in corticosteroid-naïve patients compared with those with prior corticosteroid exposure. Absence of corticosteroid background was an independent predictive factor of response to GMA. Further, in corticosteroid-naïve patients, the 1-year cumulative sustained remission rate in patients who did not receive immunomodulators was significantly higher than in patients who received immunomodulators. Accordingly, multivariate analysis revealed that immunomodulator was associated with higher risk of relapse. In conclusion, GMA was an effective treatment for corticosteroid-naïve patients and the efficacy sustained longer in those not receiving immunomodulators during GMA. GMA fulfills the notion that apheresis is to induce disease remission by removing from the body factors known to perpetuate disease. In therapeutic settings, these findings should help better decision making and avoid futile use of medical resources.

Long-interval Cytapheresis as a Novel Therapeutic Strategy Leading to Dosage Reduction and Discontinuation of Steroids in Steroid-dependent Ulcerative Colitis.

Objective This study was performed to confirm the efficacy of long-interval cytapheresis on steroid-dependent ulcerative colitis (UC). Methods To discontinue steroids in patients with steroid-dependent UC, we previously designed a novel regimen of cytapheresis (CAP), which we termed "long-interval cytapheresis (LI-CAP)", in which CAP was performed as one session every two or three weeks and continued during the whole period of tapering steroid dosage. In this study, we performed LI-CAP therapy 20 times (11 male and 9 female; mean age 41.8 years) between April 2010 and April 2015 for 14 patients with steroid-dependent UC. We evaluated the effectiveness of LI-CAP by examining the improvement in Lichtiger's clinical activity index (CAI), the rate of clinical remission, and the rate of steroid discontinuation. We further examined the rate of sustained steroid-free clinical remission at 6 and 12 months after LI-CAP in patients who successfully discontinued steroid-use after LI-CAP. The primary endpoint was the rate of discontinuation of steroids after LI-CAP. Results The mean CAI score before LI-CAP (7.550) significantly decreased to 1.65 after LI-CAP (p<0.0001). The rate of clinical remission after LI-CAP was 80%. The rate of steroid discontinuation after LI-CAP was 60.0%. The mean dose of daily prednisolone was significantly decreased after LI-CAP (2.30 mg) compared with that before therapy (17.30 mg) (p=0.0003). The rate of sustained steroid-free clinical remission after LI-CAP was 66.7% at 6 months and 66.7% at 12 months. Conclusion We confirmed that LI-CAP has therapeutic effects on reducing the dosage and discontinuing steroids in patients with steroid-dependent UC.

One year of infliximab therapy successfully improved a case of refractory pouchitis without the use of antibiotics.

A 29-year-old woman with ulcerative colitis underwent total colectomy with ileal-pouch-anal canal anastomosis in 1999. After the surgery, she developed refractory pouchitis. We administered metronidazole, mesalamine and ciprofloxacin; however, her clinical symptoms improved only very slightly. We initiated treatment with infliximab in June 2011 and discontinued the antibiotics. Thereafter, the patient's abdominal symptoms quickly improved. We discontinued the infliximab therapy in June 2012, after which time, the patient's abdominal symptoms remained in remission for 40 weeks, without the use of antibiotics. This report suggests that infliximab is useful not only for improving the clinical symptoms of refractory pouchitis, but also discontinuing antibiotic therapy in such patients.

Ulcerative colitis accompanied by idiopathic thrombocytopenic purpura and Helicobacter pylori infection.

The coexistence of idiopathic thrombocytopenic purpura (ITP) and active ulcerative colitis (UC) has been reported. We herein report a rare case of UC accompanied by ITP and Helicobacter pylori (H. pylori) infection. A female UC patient was diagnosed with ITP. At that time, the UC was almost in remission and we suspected that the ITP was caused by some factor other than UC. Accordingly, we found H. pylori infection and administered H. pylori eradication therapy. Consequently, the patient's serum platelet count recovered dramatically. Our report demonstrates the importance of conducting examinations for H. pylori infection in ITP patients, even those with UC.

Molecular cloning reveals nearly half of patients with Crohn's disease have an antibody to peroxiredoxin 6-like protein.

BACKGROUND AND AIM: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. We aimed to identify the etiological agent of CD using a molecular cloning strategy that was particularly focused on identifying agents causing immune abnormalities and infectious agents. METHODS: We constructed a cDNA library derived from the inflamed intestinal tissue of a CD patient, and screened 1.5 million clones in this library with the serum from another typical CD patient. The expressed cDNA clones that positively reacted with the serum were then expressed as fusion proteins with glutathione S-transferase, and western blotting was performed using the sera of 22 CD, 13 ulcerative colitis (UC), and 16 non-IBD patients. RESULTS: We identified nine positive clones that did not contain any viral or bacterial genomic DNA. Of these, we selected one clone (clone 50) with which the typical CD patient's serum most strongly reacted. Clone 50 is highly homologous to the antioxidant protein peroxiredoxin 6. In western blotting, the sera of 47.6% CD patients (small intestine type 80%, large and small intestine type 43%, large intestine type 0%) showed strong reactivity to clone 50, none of the UC patients were reactive to clone 50, and 18.8% of non-IBD patients were very weakly reactive to it. We also found that the expression of peroxiredoxin 6 was significantly increased in inflamed intestinal epithelia of CD. CONCLUSION: The present study first showed that some CD patients have an antibody against peroxiredoxin 6-like protein, which may be involved in the pathogenesis of CD.

Typical gastroduodenal endoscopic findings in a Crohn's disease patient in remission stage.

A 39-year-old patient with Crohn's disease (CD) was referred to our hospital for maintenance treatment of CD. He was diagnosed as having CD of the small and large intestines at 32 years old. He underwent partial resection of the ileum at 35 years old because of ileal perforation. He had received enteral nutritional supplement (1200 kcal/d) and metronidazole preparation (500 mg/d), and was in remission Crohn's disease activity index 73. We performed a routine gastroduodenal endoscopic examination, which revealed the representative endoscopic findings of gastroduodenal lesions in CD, namely, bamboo-joint-like appearance of the gastric body and cardia and a notched sign in the duodenum. These findings were clearly observed by using indigo carmine dye spraying. In our patient, typical gastroduodenal findings were observed even in the remission stage, suggesting that these findings would contribute to the early diagnosis of CD not only in the active stage but also during remission.

Wound healing of intestinal epithelial cells.

The intestinal epithelial cells (IECs) form a selective permeability barrier separating luminal content from underlying tissues. Upon injury, the intestinal epithelium undergoes a wound healing process. Intestinal wound healing is dependent on the balance of three cellular events; restitution, proliferation, and differentiation of epithelial cells adjacent to the wounded area. Previous studies have shown that various regulatory peptides, including growth factors and cytokines, modulate intestinal epithelial wound healing. Recent studies have revealed that novel factors, which include toll-like receptors (TLRs), regulatory peptides, particular dietary factors, and some gastroprotective agents, also modulate intestinal epithelial wound repair. Among these factors, the activation of TLRs by commensal bacteria is suggested to play an essential role in the maintenance of gut homeostasis. Recent studies suggest that mutations and dysregulation of TLRs could be major contributing factors in the predisposition and perpetuation of inflammatory bowel disease. Additionally, studies have shown that specific signaling pathways are involved in IEC wound repair. In this review, we summarize the function of IECs, the process of intestinal epithelial wound healing, and the functions and mechanisms of the various factors that contribute to gut homeostasis and intestinal epithelial wound healing.

[Marked efficacy of metronidazole for the intestinal pseudoobstruction associated with systemic sclerosis].

In May 2009, a 57-year-old woman who had rheumatoid arthritis since 9 years was admitted to our hospital for dyspnea due to interstitial pneumonia (IP). On admission, she exhibited proximal scleroderma, finger edema, Raynaud's phenomenon, digital pitting scars, ankyloglossia, and esophageal dysmotility. The patient was diagnosed as having systemic sclerosis (SSc), according to the American College of Rheumatology criteria. After initiation of high-dose corticosteroid therapy, gradual amelioration of IP was observed. However, the patient complained of abdominal fullness. Computed tomography and intestine series findings revealed significant dilatation of the small intestine due to intra-abdominal free air and pneumatosis cystoides intestinalis but no mechanical obstruction, leading to a diagnosis of SSc with pseudo-obstruction. The patient underwent decompression with a long intestinal tube, which led to improvement in her symptoms. Although erythromycin (EM) and some prokinetic agents were administered, abdominal involvement recurred several days after resumption of oral ingestion. Therefore, we changed the antibiotic from EM to metronidazole (750 mg/day). Her manifestations were promptly ameliorated by metronidazole therapy in 4 days and did not recur. Metronidazole is an antibiotic used to treat intra-abdominal anaerobic bacterial infections and is also commonly used in preoperative treatment for colorectal surgery. In conclusion, we report a case where SSc-associated pseudo-obstruction was successfully managed by metronidazole therapy.

Epimorphin protects hepatocytes from oxidative stress by inhibiting mitochondrial injury.

BACKGROUND AND AIMS: Many investigations have demonstrated that cell injuries caused by generation of reactive oxygen species (ROS) is a common mechanism of various hepatic disorders. Recently, we have demonstrated that epimorphin, originally cloned as a mesenchymal protein, protects cultured intestinal epithelial cells from ROS. We therefore examine whether epimorphin protects primary cultured hepatocytes from ROS-induced cell injury. METHODS: We explored the cell viability and the intracellular ROS levels of purified murine hepatocytes after exposure to 0.5 mM H(2)O(2) with or without pretreatment of epimorphin. Then, we observed mitochondrial permeability transition (MPT) and depolarization using confocal microscopy to make clear the mechanism that epimorphin inhibited cell injuries after exposure to H(2)O(2). In addition, to clarify the signaling pathways related to cell survival, we carried out Western blotting analysis with phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) polyclonal antibody to evaluate the inhibition of JNK by epimorphin. Finally, we evaluated the cell viability in hepatocytes administered JNK inhibitor. RESULTS: Epimorphin protected primary cultured hepatocytes from H(2)O(2)-induced cell injuries independent of intracellular ROS levels. Epimorphin also inhibited onset of MPT, depolarization of the mitochondrial membrane potential, and eventually cell killing. The cell protective function of epimorphin after exposure to H(2)O(2) was not dependent on Akt signaling but on JNK signaling. CONCLUSION: Epimorphin can protect hepatocytes from MPT-dependent cell injury induced by ROS. Since hepatic disorders could be caused by MPT-dependent cell injuries with excessive ROS, epimorphin might open a new therapeutic avenue for hepatic disorders.

Acute respiratory distress syndrome associated with severe ulcerative colitis.

Various extraintestinal manifestations including pulmonary abnormalities have been reported in patients with ulcerative colitis. Acute respiratory distress syndrome (ARDS) is a serious and fatal pulmonary manifestation. We have experienced a 67-year-old male patient with ARDS associated with a severe type of ulcerative colitis (UC). Severe dyspnea symptoms occurred during the treatment of UC in a previous hospital and the patient was transferred to our hospital on June 27, 2007. Both blood and sputa cultures for bacteria and fungi were negative. Cytomegalovirus antigenemia was also not detected. From the clinical and radiological [Chest X-ray, computed tomography (CT)] findings, the patient was diagnosed with ARDS on the basis of the definition of ARDS developed by the European-American Consensus Conference on ARDS. Both colonic inflammations and ARDS symptoms of the patient were resistant to any medical treatment including corticosteroids and antibiotics. However, ARDS symptoms were dramatically improved after surgical colectomy. We believe that severe colonic inflammation from UC was closely associated with the onset of ARDS of the patient. Our case report suggests that a severe type of ulcerative colitis might be taken into consideration as one of the predisposing factors of ARDS.

An open-label prospective randomized multicenter study shows very rapid remission of ulcerative colitis by intensive granulocyte and monocyte adsorptive apheresis as compared with routine weekly treatment.

OBJECTIVES: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active ulcerative colitis (UC). However, with routine weekly treatment, it may take several weeks to achieve remission, and to date, the efficacy of a more frequent treatment schedule remains unknown. The aim of this study was to assess the clinical efficacy and safety of intensive GMA treatment in patients with active UC. METHODS: This was an open-label, prospective, randomized multicenter study to compare an intensive, two GMA sessions per week, with the routine, one GMA session per week. A total of 163 patients with mild-to-moderately active UC were randomly assigned to routine weekly treatment or intensive treatment. The maximum number of sessions of GMA permitted was 10. However, when patients achieved remission, GMA was discontinued. Remission rate at the end of the study, time to remission, and adverse events were assessed in both groups. RESULTS: Of the 163 patients, 149 were available for efficacy analysis as per protocol, 76 were in weekly GMA, and 73 were in intensive GMA. At the end of the study period, clinical remission was achieved in 41 of 76 patients (54.0%) in weekly GMA and in 52 of 73 patients (71.2%) in intensive GMA (P=0.029). The mean time to remission was 28.1+/-16.9 days in the weekly GMA treatment group and 14.9+/-9.5 days in the intensive GMA group (P<0.0001). Intensive GMA was well tolerated without GMA-related serious adverse side effects. CONCLUSIONS: Intensive GMA in patients with active UC seems to be more efficacious than weekly treatment, and significantly reduced the patients' morbidity time without increasing the incidence of side effects.

Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis.

AIM: Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten-deficient mice and the underlying mechanisms. METHODS: At 40 weeks, livers from male and female Pten-deficient mice were processed for measuring lipid content, genes expression analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Seventy-six-week-old mice were used in tumor burden experiments. RESULTS: Hepatic steatosis, inflammation, and even carcinogenesis in Pten-deficient mice were attenuated in females compared to males. Attenuated fatty liver in females was ascribed to inactivation of sterol regulatory element binding protein-1c. Hepatic inflammation in females was suppressed via decreased ROS with increased antioxidant gene expression and decreased proinflammatory cytokine production. Anti-cancer effect in female mice was, at least in part, due to the significantly lower ratio of oleic to stearic acid in the liver. CONCLUSIONS: Hepatic lesions in Pten-deficient mice were attenuated in females compared to males, as were human NAFLD and NASH. Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens.

Morphogenic protein epimorphin protects intestinal epithelial cells from oxidative stress by the activation of EGF receptor and MEK/ERK, PI3 kinase/Akt signals.

Epimorphin is a mesenchymal protein that regulates morphogenesis of epithelial cells. Our preliminary study suggested a novel function of epimorphin in enhancing survival of intestinal epithelial cells (IEC). Oxidative stress leads to cell injury and death and is suggested to be a key contributor to pathogenesis of inflammatory bowel disease. This study was conducted to determine whether epimorphin protects IEC from oxidative stress. Rat intestinal epithelial cell line IEC-6 was cultured with epimorphin (10 and 20 mug/ml), and the life span of IEC was assessed. The mean life span of IEC-6 cells was prolonged 1.9-fold (P < 0.0006) by treatment with epimorphin. We then examined the epimorphin signaling pathways. Epimorphin phosphorylated epidermal growth factor (EGF) receptor, activated the MEK/extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and phosphatidylinositol 3 (PI3) kinase/Akt pathways, phosphorylated Bad, and induced Bcl-X(L) and survivin. Hydrogen peroxide (1 mM) induced cell death in 92% of IEC-6 cells, but epimorphin dramatically diminished (88.7%) cell death induced by hydrogen peroxide (P < 0.0001). This protective effect of epimorphin was significantly attenuated by inhibitors of MEK and PI3 kinase (P < 0.0001) or EGF receptor-neutralizing antibody (P = 0.0007). In wound assays, the number of migrated cells in the wound area decreased (72.5%) by treatment with 30 muM hydrogen peroxide, but epimorphin increased the number of migrated cells 3.18-fold (P < 0.0001). These results support a novel function of epimorphin in protecting IEC from oxidative stress. This anti-oxidative function of epimorphin is dramatic and is likely mediated by the activation of EGF receptors and the MEK/extracellular signal-regulated kinase and PI3 kinase/Akt signaling pathways and through the induction of anti-apoptotic factors.