Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease.

Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn's disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 µg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 µg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4-14 days after ADA administration was ≥9.2 µg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 µg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.

Highly Bioavailable Curcumin Derivative Ameliorates Crohn's Disease Symptoms: A Randomized, Double-Blind, Multicenter Study.

BACKGROUND & AIMS: The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease. METHODS: In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. RESULTS: In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. CONCLUSIONS: Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease. CLINICAL TRIAL UMIN REGISTRATION ID: UMIN000015770.

Assessment of Long-Term Efficacy and Safety of Adalimumab in Patients with Ulcerative Colitis: Results from a 6-Year Real-World Clinical Practice.

BACKGROUND: Although evidence for the short- to medium-term efficacy of adalimumab in ulcerative colitis (UC) patients is emerging, there are a limited number of reports on the long-term efficacy of adalimumab. This study was to understand baseline demographic features, which potentially could be risk factors for relapse or colectomy following induction of remission by adalimumab in UC patients. Additionally, factors affecting long-term outcomes were to be identified. METHODS: Twenty-one patients with UC who had been treated with adalimumab were reviewed retrospectively. Comparative analyses were undertaken by factoring steroid withdrawal versus non-withdrawal, long-term remission versus relapse following remission, and requiring surgical intervention for UC versus surgery-free. RESULTS: Adalimumab treatment was associated with steroid tapering in steroid-dependent cases in the long term. Of the 14 patients in whom clinical remission was achieved, the cumulative nonrelapse survival rate at 350 weeks was 43.8% and the cumulative nonoperative survival rate was 85.7%. Risk factors for surgery included intolerance to salicylates (p = 0.005) and past treatment with tacrolimus (p = 0.023). CONCLUSIONS: Adalimumab treatment was associated with long-term efficacy in patients with mild UC - patients achieved a high cumulative nonoperative survival rate over a long period of time, beyond 6 years.

Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis.

OBJECTIVES: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. METHODS: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. RESULTS: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age ≤60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naïve UC, and biologic naïve UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). CONCLUSIONS: GMA appeared to be effective in steroid naïve and biologic naïve patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings.

NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.

BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

Adsorptive Depletion of Myeloid Lineage Leucocytes as Remission Induction Therapy in Patients with Ulcerative Colitis after Failure of First-Line Medications: Results from a Three-Year Real World, Clinical Practice.

BACKGROUND/AIMS: In patients with active ulcerative colitis (UC), pharmacologics, although initially effective in most patients, are associated with refractoriness, loss of response or unfavourable side effects as additional morbidity factors. Depletion of myeloid lineage leucocytes like the CD14(+)CD16(+) monocyte phenotype, which is a major source of tumour necrosis factor-α, by granulocyte/monocyte apheresis (GMA) if effective, is also known to be free from side effects. METHODS: In clinical practice setting, 77 consecutive patients with moderate to severe UC, who failed to respond to first-line medications received GMA with the Adacolumn as remission induction therapy. Patients who achieved remission were followed for 3 years. RESULTS: Among the 77 patients, 46.8% were corticosteroids-naïve, 26% corticosteroid-dependent and 27.3% corticosteroid-refractory. The overall clinical remission rate was 79.2%, and the overall mucosal healing (MH) rate according to the Mayo endoscopic subscore ≤1 was 58.5%. MH rates in corticosteroid-naïve, corticosteroid-dependent and corticosteroid-refractory subgroups were 70.8, 56.3, and 38.5%, respectively. The 3-year sustained clinical remission rates in corticosteroid-naïve, corticosteroid-dependent and corticosteroid-refractory subgroups were 83.3, 68.8, and 23.1%, respectively. CONCLUSION: Corticosteroid-naïve patients appeared to benefit the most from the Adacolumn GMA, and attain a favourable long-term clinical course. Accordingly, GMA should be a first-line therapy in this clinical setting.

The Ulcerative Colitis Endoscopic Index of Severity More Accurately Reflects Clinical Outcomes and Long-term Prognosis than the Mayo Endoscopic Score.

BACKGROUND AND AIMS: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo endoscopic score (Mayo ES) are used to evaluate ulcerative colitis (UC) severity. This study compared UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with the aim of predicting medium- to long-term prognosis. METHODS: Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. An index of clinical activity and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. Changes in UCEIS and Mayo ES before and after induction therapy were compared. RESULTS: The mean UCEIS improved from 6.2±0.9 to 3.4±2.1 (p < 0.001). Based on the UCEIS, a significant reduction was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect a significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; the Mayo ES seems to miss these early changes. In other words, whereas the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers and is 3 (severe UC) for both deep and shallow ulcers. Additionally, better UCEIS strata after induction therapy were associated with lower incidences of colectomy (p = 0.0001) or relapse (p = 0.0008). CONCLUSIONS: The UCEIS accurately reflects clinical outcomes and predicts the medium- to long-term prognosis in UC patients undergoing induction therapy. These findings should support decision-making in clinical practice settings.

An Increased Serum N-Terminal Telopeptide of Type I Collagen, a Biochemical Marker of Increased Bone Resorption, Is Associated with Infliximab Therapy in Patients with Crohn's Disease.

BACKGROUND: Osteopenia and osteoporosis are considered to be extra-intestinal manifestations of inflammatory bowel disease (IBD). Anti-tumor necrosis factor (TNF)-α biologics have been introduced as novel medications for an active IBD. However, it is still not well documented whether anti-TNF-α affects the frequency of bone loss or abnormality of bone mineral markers among patients with IBD. AIMS: This study was to investigate the biochemical basis of low bone mineral density (BMD) and increased turnover in IBD during infliximab (IFX) therapy. METHODS: Forty patients with Crohn's disease (CD), 80 patients with ulcerative colitis (UC), and 65 age- and gender-matched controls were included. BMD was measured with dual-energy X-ray absorptiometry, and vitamins K and D were measured as serum undercarboxylated osteocalcin (ucOC) and 1,25-(OH)2D, respectively. Bone formation and resorption were based on measuring bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), respectively. RESULTS: Significantly lower BMD was found in patients with UC and CD as compared to controls (P < 0.05). BAP, 1,25-(OH)2D, ucOC, and NTx were significantly higher in CD patients, but not in UC patients as compared to controls (P < 0.05). Further, serum NTx level was significantly higher in CD patients who were receiving IFX as compared to CD patients who were not receiving IFX (P < 0.01). CONCLUSIONS: A lower BMD and higher bone metabolism markers were found in CD patients as compared to controls or UC patients. A significant increased serum level of NTx, a biochemical marker of increased bone resorption, was observed in CD patients during IFX therapy.

Tacrolimus for remission induction in ulcerative colitis: Mayo endoscopic subscore 0 and 1 predict long-term prognosis.

BACKGROUND: Tacrolimus has shown efficacy in patients with ulcerative colitis. AIMS: To evaluate the efficacy of tacrolimus as remission induction therapy and assess medium to long-term outcomes in patients who achieve remission. METHODS: Forty-four ulcerative colitis patients who were treated with tacrolimus in three institutes during 2009-2013 were retrospectively reviewed. Short-term efficacy was based on the clinical activity index and the Mayo endoscopic subscores. Clinical activity index≤4 meant clinical remission, while Mayo endoscopic subscore 0 or 1 meant mucosal healing. Medium to long-term prognosis was based on relapse free survival in relation to the Mayo endoscopic subscore and duration of tacrolimus therapy in patients who achieved remission. RESULTS: At 12 weeks, clinical remission was achieved in 29 of 44 patients (65.9%). Thirty-two patients received endoscopic evaluations, and mucosal healing rate was 43.8%. Among patients with clinical remission, mucosal healing rate was 60.9%. Relapse-free survival at 6, 12, and 24 months were 66%, 56%, and 50%, respectively, and was higher in patients on long-term tacrolimus (over 4 months, P=0.03), and patients with better endoscopic subscore (P=0.009). CONCLUSIONS: Mucosal healing observed within 12 weeks or after a longer duration of tacrolimus therapy was associated with significantly better remission maintenance time.

Looking for endoscopic features of cytomegalovirus colitis: a study of 187 patients with active ulcerative colitis, positive and negative for cytomegalovirus.

BACKGROUND: Cytomegalovirus (CMV) is frequently detected in ulcerative colitis (UC) lesions of steroid-refractory patients. This has led to the suspicion that CMV might cause colitis and steroid refractoriness. METHODS: During 2003 and 2011, 187 consecutive patients were divided into group I (n = 105), corticosteroid-free and thiopurine-free in the past 6 months, and group II (n = 82), all corticosteroid refractory. The combination of serum CMV immunoglobulin (Ig)M, CMV IgG, CMV antigenemia (Ag), and real-time polymerase chain reaction assays were performed to identify CMV(+) patients. RESULTS: In group I, 79 patients were CMV IgG(+) and 26 patients were CMV IgG(-) and CMV IgM(-). In group II, 61 patients were CMV IgG(+), 1 CMV IgM(+), and 20 CMV IgG(-) and CMV IgM(-). All CMV IgG(+) patients were screened for CMV Ag. In group I, 6 of the 79 CMV IgG(+) patients were CMV Ag(+). In group II, 27 patients were CMV Ag(+). Colonoscopy was performed in all patients before screening for CMV. Similar colonoscopic features including punched out ulcers, geographic ulcers, and irregular ulcers were found in both CMV(+) and CMV(-) patients, without any striking difference between the 2 groups. CONCLUSIONS: CMV reactivation might be encouraged by immunosuppressive drugs, like corticosteroids, immunomodulators, and therefore, patients with UC are at a high risk of CMV reactivation, potentially exacerbating UC. However, this study of 187 patients, CMV(+) and CMV(-), could not find colonoscopic features unique to CMV, except that CMV might be one factor for steroid refractoriness, and UC exacerbation.

A new paradigm in ulcerative colitis: regulatory T cells are key factor which induces/exacerbates UC through an immune imbalance.

Leukocytapheresis (LCAP) appears to remove or inactivate inflammatory cells and to reset immunological responses, resulting to cure responders of ulcerative colitis (UC). The changes of T cell subsets were investigated in UC patients treated with LCAP. Levels of T cell subsets in peripheral blood before and after LCAP were analysed by flow cytometric analysis. Of 20 UC patients, 13 (65%) achieved remission and 2 (10%) showed the improvement of UC symptoms. Ratios of some T cell subtypes such as regulatory T (Treg) cells and memory T cells to CD4(+) T cells changed significantly only in responders. Especially, ratio of resting Treg/CD4(+) T cells was significantly increased after the first LCAP session, and then one of activated Treg/CD4(+) T cells was increased after 2 week. This may lead to the development of a new UC paradigm in which an imbalance in Treg cell subsets triggers the onset and/or exacerbation of UC.

[A case of colonic obstruction due to post-operative stenosis of the colon and multiple enteroliths].

An 81-year-old man who had under gone two abdominal surgeries and temporary colostomy 30 years previously was admitted due to lower abdominal pain and vomiting. An abdominal X-ray film and abdominal CT scan showed intestinal distension and multiple calcareous deposits in the colon. Gastrografin enema examination revealed smooth stenosis at the sigmoid colon and many additional defects. Endoscopy could not be performed due to the stenosis. He did not agree to surgery. Seven months later, he was admitted again, due to colonic obstruction. Surgery was performed which revealed colonic obstruction as the source of post-operative stenosis of the sigmoid colon and multiple enteroliths. The stones consisted of a core and a hull and contained ammonium magnesium phosphate.