Thalidomide is effective in inducing clinical remission in children and adolescents with refractory Crohn’s disease (CD). However, the efficacy and safety of thalidomide in adult patients with refractory CD to maintain clinical remission remain unclear. Seventy-nine consecutive adult CD patients in remission, who were refractory or intolerant to thiopurines and dependent on steroid before, were retrospectively enrolled. Thalidomide (50–100 mg/day) was administrated to maintain clinical remission. Patients who were induced by other immunosuppressants before would continue the concomitant therapy in low dose. Primary outcome was the time of clinical relapse that defined as the Harvey–Bradshaw Index (HBI) scores >4. Mucosal healing after thalidomide treatment was defined as simplified endoscopic activity scores for CD (SES-CD) = 0. By Week 48, the clinical remission rate was 70.89% out of all the 79 patients. Normalisation of high-sensitivity C-reactive protein levels (hs-CRP) at baseline (adjusted relative risk, 5.209; 95% CI, 1.402–19.349; p = 0.014) predicted the efficacy of remission maintenance (Figure 1). Forty-four patients consented to undergo colonoscopy at the time before and after thalidomide treatment. The mucosal healing rates after thalidomide treatment was 14.63% (Figure 2). Adverse events occurred in 54 (68.35%) patients, but only 8 (10.13%) patients had to discontinue therapy. None of the side effect was irreversible. Proportion with remission in patients that stratified by the normalisation of hsCRP levels at baseline. p-value and RR were calculated for comparison between two groups in Log-Rank test and Cox proportional hazard model, which were adjusted for disease duration and disease behavior. Colonoscopies of patients who got mucosal healing after thalidomide therapy. 1A, 2A, and 3A were three patients' colonoscopies before treatment. 1B, 2B, and 3B were the patients' colonoscopies after thalidomide treatment, respectively. Low-dose thalidomide was efficacious in maintaining clinical remission in 48 weeks and achieving mucosal healing in adult patients with refractory CD. The patients with normal hs-CRP levels at baseline may have a longer duration of clinical remission maintenance. The side effects of thalidomide were mild, tolerable, and reversible. Therefore, thalidomide may be an alternative candidate for adult refractory CD patients.
To the Editors, A 24-year-old man presenting with a history of abdominal discomfort, poor appetite, and progressive weight loss was admitted to our hospital. Crohn’s disease (CD) was suspected. He was not taking any medication for CD. Colonoscopy revealed multiple ulcers located from the cecum to the rectum, and typical longitudinal ulcers were found in the descending colon (Figure 1A). The diagnosis of CD was confirmed by pathological examination. When we performed computed tomography enterography (CTE) for this patient, we found several unexpected low-density liver lesions (Figure 2A), in addition to the small bowel and colon lesions that reflected CD (Figure 1B and C). The magnetic resonance imaging (MRI) scan confirmed these changes. Multiple long T1 and long T2 signal foci were observed in the S2, S5, S6, and S8 areas in the liver. The most significant lesion measured 40 mm × 33 mm...
Summary Background Thiopurine‐induced leukopenia is the most common dangerous adverse event in Asians. NUDT 15 R139C was recently proposed to be a promising biomarker for leukopenia with thiopurine therapy in Asians, but this has not been replicated in the Chinese population. Aim To investigate the influence of NUDT 15 R139C, thiopurine S‐methyltransferase ( TPMT ), 6‐ TGN and 6‐ MMPR on thiopurine‐induced leukopenia in Chinese patients with Crohn's disease. Methods Clinical and epidemiological characteristics were reviewed from medical records. NUDT 15 R139C and TPMT were genotyped. 6‐ TGN /6‐ MMPR concentrations were measured with high‐performance liquid chromatography ( HPLC ). Results A total of 253 patients were included, 65 (25.7%) of whom experienced leukopenia. The median follow‐up with thiopurine treatment was 38.0 weeks (range, 1–192 weeks). NUDT 15 R139C was strongly associated with the incidence of leukopenia (70.2% mutation vs. 12.8% wild type; P =8.61×10 −19 ; odds ratio, 10.80; 95% CI , 5.89–19.83). However, TPMT genotype was not found to be correlated with the incidence of leukopenia ( P = 0.44). In subgroup of NUDT 15 wild type, there was significant difference of 6 TGN concentration between patients with and without leukopenia (413.0 (174.2–831.4) vs. 279.7 (77.3–666.9) pmol/8 × 10 8 RBC , P = 0.0055). In contrast, no association was found in patients with NUDT 15 R139C variant alleles ( P = 0.26). 6‐ MMPR was not correlated with leukopenia ( P = 0.84). Conclusions In Chinese patients, it is strongly recommended to detect NUDT 15 genotype rather than TPMT before initiating thiopurine drugs. 6 TGN concentration should be routinely monitored in CD patients with NUDT 15 wild type. As for CT genotype, starting at low dose and careful monitoring for leukopenia and 6 TGN levels is recommended.
Summary Introduction Thiopurine S‐methyltransferase (TPTM) is a well known biomarker for thiopurine‐induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. Aims To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine‐induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. Methods Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine‐induced leucopenia (<3.5 × 10 9 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid‐free remission at week 36. Results The rate of thiopurine‐induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53‐1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28‐0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow‐up. Conclusions Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine‐induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.
Abstract Lipid metabolism disorder is a critical feature of Crohn’s disease (CD). Phosphatidylinositol (PI) and its derivative, phosphatidylinositol bisphosphate (PIP2), are associated with CD. The mechanisms underlying such association remain unknown. In this study, we explored the role played by the major PI derivative, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], in CD pathogenesis. The relationship between CD activity and PI or PIP2 was analyzed via lipidomics. The mucosal expression of PI(4,5)P2 in patients with CD was measured using immunofluorescence. The function and mechanism of PI(4,5)P2 were examined in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-induced Caco-2 cell models, along with MeRIP and mRNA sequencing. The results suggested lipid PI and PIP2 were substantially negatively associated with disease activity and high-sensitivity C-reactive protein. PI(4,5)P2 was substantially downregulated in the inflamed mucosa of patients with CD. PI(4,5)P2 alleviated mouse colitis, with improvements in survival rate, colon length, weight, and disease activity index. PI(4,5)P2 also alleviated DSS-induced tissue damage, tight junction loss, and intestinal epithelial cell (IEC) pyroptosis. In the in vitro LPS-induced cell model, PI(4,5)P2 inhibited pyroptosis, as well as NLRP3, and caspase-1 expression, in addition to reducing interleukin (IL)-18, IL-1β, and lactate dehydrogenase (LDH) secretion. PI(4,5)P2 mediated NNMT upregulation in mice and Caco-2 cells and suppressed pyroptosis in IECs. NNMT knockdown restricted the inhibitory effect of PI(4,5)P2 on IEC pyroptosis. NNMT inhibited the stability of RBP4 mRNA via m6A modification, thereby preventing pyroptosis following PI(4,5)P2 treatment. Significant correlations were also observed between PI(4,5)P2 and NNMT, NNMT and RBP4, and RBP4 and GSDMD expression in the intestinal tissues from patients with CD. Our results indicated that PI(4,5)P2 ameliorates colitis by inhibiting IEC pyroptosis via NNMT-mediated RBP4 m6A modification. Thus, PI(4,5)P2 shows potential as a therapeutic target in CD.
Crohn's disease (CD), a type of inflammatory bowel disease, is a chronic idiopathic disorder of the gastrointestinal tract with an increasing global incidence. Exclusive enteral nutrition (EEN) is a diet therapy that is effective in the management of active CD with unknown etiology. Lipid metabolism plays an important role in CD and may be associated with EEN treatment. This study compared the plasma lipid profiles before and after EEN in adults with active CD to those of healthy controls (HCs).Eleven adult patients with active CD who received enteral nutrition formula treatment for 12 weeks were included, along with 17 HCs. The profiles of 869 plasma lipid species were measured, and inflammatory and nutrition-associated indices were evaluated in the patients.Nine patients achieved clinical remission following 12 weeks of EEN treatment, and four achieved mucosal healing. Before EEN, 80 lipid species and 17 lipid classes were significantly different between patients with CD and HCs. After EEN treatment, 103 lipid species and 12 lipid classes were significantly different between patients with CD and HCs. Significant changes in 7 lipid classes and 38 lipid species were observed between the pre- vs. post-treatment CD patients. The levels of simplified glucosylceramide series, monogalactosyldiacylglycerol, phosphatidylinositol, phosphatidylserine, and phosphatidylcholine increased, while those of phosphatidylglycerol and phosphatidylinositol diphosphate decreased significantly after EEN. These lipid classes and species were associated with the inflammatory and nutritional indices. Pathway analysis suggested the metabolism of arachidonic acid, glycerophospholipids, linoleate, and phosphatidylinositol phosphate was related to the EEN mechanism.EEN induces alterations in multiple lipid classes and species, leading to clinical improvements. Lipid metabolism may be involved in the EEN anti-inflammatory effect.
Objectives We aimed to evaluate the effectiveness and safety of clinical decision support tool (CDST)‐guided initial selective intensive induction therapy (IIT) for patients with Crohn's disease (CD) who were treated with ustekinumab (UST) and to identify those most likely to benefit from IIT. Methods Patients with active CD were included in this multicenter retrospective study and were categorized as low‐, intermediate‐, and high‐probability responders according to the UST‐CDST. IIT was defined as intensive induction by two or three initial doses of weight‐based intravenous UST administration. Patients treated with standard therapy (ST) served as controls. The primary end‐point was corticosteroid‐free clinical remission (CFCR) at Week 24. Secondary end‐points included clinical remission, clinical response, endoscopic remission, endoscopic response, and C‐reactive protein (CRP) normalization at Week 24. Propensity score adjustments was conducted to ensure comparability. Results A total of 296 patients were included. At Week 24, IIT was associated with higher rates of CFCR (72.3% vs 43.0%, p < 0.001), clinical remission (77.3% vs 47.1%, p < 0.001), clinical response (78.1% vs 60.1%, p = 0.001), endoscopic remission (26.1% vs 9.9%, p = 0.024), and endoscopic response (58.6% vs 36.9%, p = 0.018) in low–intermediate‐probability responders compared with ST. CRP normalization was comparable between groups. No significant differences were found in any end‐points in high‐probability responders. No serious adverse events were observed. Conclusion The efficacy of IIT was superior to that of ST in patients with predicted poor response to UST, which may be regarded as a novel strategy for stratifying patients at baseline.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)