Abstract
Background
The short-term effects of teduglutide (TED) for short bowel syndrome with chronic intestinal failure (SBS–IF) in patients with Crohn’s disease (CD) remain unknown and real-world ...data have not been scarce. This study aimed to investigate the short-term efficacy and safety of TED in CD patients on parenteral support (PS) for SBS–IF.
Methods
We retrospectively investigated the medical records of CD patients with SBS–IF who initiated TED between January 2020 and October 2022 in Hyogo Medical University hospital. The primary outcomes were the change in PS volume and proportion of patients with a reduction of PS volume by ≥20% at week 4. Secondary outcomes were the changes in body mass index (BMI), estimated glomerular filtration rate (eGFR), albumin, hematocrit (Ht), PS calorie requirements, withdrawal from PS, and adverse events during the observation period.
Results
Of 605 CD patients, 23 who underwent home PS for SBS–IF were included in this study. Twenty patients continued TED throughout the observation period. The median PS duration was 11.6 (range 1.0-20.0) years and the observation period after starting TED was 48.0 (7.0-60.0) weeks. TED significantly reduced the PS volume from 17989(570-49000) mL/week to 14257(0-42000) mL/week at week 4 (p = 0.0013), and the PS volume decreased by ≥20% in 8 patients (40.0%) at week 4 and in 16 patients (80.0%) during the observation period after TED administration. The BMI significantly increased from 17.9 (12.9–23.9) kg/m2 before TED administration and 18.9 (14.6–25.4) kg/m2 after TED administration (p = 0.014). Although there were no significant differences in albumin (p = 0.53), eGFR (p = 0.66), and Ht (p = 0.089), the PS calorie /week was significantly decreased from 6581 (244–14000) kcal to 3747(0– 8820) kcal after TED administration (p = 0.0001). Ten patients (50.0%) experienced gastrointestinal stoma complications, including stoma swelling and/or prolapse during the observation period. Abdominal pain occurred in 7 cases (35.0%), catheter-related infection in five patients (25.0%), oedema in 4 patients (20.0%), nausea in 2 patients (10.0%), abdominal distension in 3 patients (15.0%), and upper respiratory tract infection in 1 patient (5.0%). All the symptoms were transient and tolerable. Although 3 patients discontinued TED due to nausea and abdominal pain and were excluded from this analysis, these symptoms improved after the discontinuation.
Conclusion
TED reduced PS volume at week 4 in CD patients with SBS–IF, and the BMI and the PS calorie requirement were improved during the observational period without serious adverse events.
Abstract
Background
Fistulising perianal diseases (FPD) are common in patients with Crohn's disease (CD) in Asia, but the treatment pattern and the proportion of patients who develop new FPD after ...diagnosis are not clear. An interim analysis of a large registry study was performed to evaluate the difference in prognosis between patients with and without FPD at diagnosis of CD and the incidence and timing of onset of FPD in patients without FPD at diagnosis of CD.
Methods
iCREST-CD is a prospective, non-interventional, longitudinal, observational registry study conducted at 19 tertiary centres in Japan. Patients newly diagnosed with CD from June 2016 to June 2020 based on the diagnostic criteria of the Japanese Guidelines, aged ≥16 years at the time of informed consent with no prior exposure to biologics were enrolled. Patient demographics, clinical data, disease activity and medical treatment record up to June 2022 were used. FPD were defined as a perianal abscess and/ or perianal fistula.
Results
Of the 662 patients with newly diagnosed CD for whom with or without FPD were recorded, 236 patients 35.6% had FPD at diagnosis (Group A). Of the 426 patients who did not have FPD at the time of diagnosis, 32 patients developed FPD during the observation period (Group B), and 394 patients did not develop it (Group C). The mean age SD at the time of CD diagnosis in Groups A, B, and C was 25.0 8.6, 31.6 15.5, and 31.7 14.4 years, respectively. The proportion of female was 21.2%, 34.4% and 37.8%, respectively; L2 disease location was 14.6%, 23.3%, and 18.0%, respectively; and B2+B3 disease behaviour was 27.5%, 53.1%, and 40.6%, respectively. The mean CRP (mg/L SD) was 28.5 33.8, 42.4 43.6, and 27.1 36.3, respectively. For disease activity based on HBI score, the proportion with moderate (8≦HBI≦16) and severe (16<HBI) activity was 17.6%, 36.8%, and 24.0%, respectively (Table).
The rate of patients who developed FPD was 4.5% (19 patients) by 12 months and 6.5% (28 patients) by 24 months, respectively (Figure).
In Group A with a mean observation period (month SD) of 27.9 8.8, 12.3% and 17.3% of patients needed perianal surgery at 12 and 24 months, respectively. In Group B with a mean observation period of 29.7 7.7, 7 FPD patients 21.9% subsequently underwent perianal surgery, all within 12 months of FPD onset.
Conclusion
Patients who did not have a perianal abscess or fistula at the time of their CD diagnosis but later developed these problems tended to have numerically higher CD activity at the time of diagnosis and were more likely to require perianal surgery. These results suggest that patients with highly active CD are at risk of developing new FPD and should be carefully monitored.
Abstract
Background
Biologics are commonly used for the treatment of Crohn’s disase (CD); however, the proportion of biologics used and their initiation time from diagnosis differs widely between ...different regions. There is limited information about the patient characteristics and the treatment persistence of each initial biologics, and the treatment persistence of top-down and step-up therapy. iCREST-CD is a prospective, non-interventional, longitudinal, observational registry study conducted at 19 tertiary centres to understand the characteristics of CD treatments in actual clinical settings in Japan. We conducted an interim analysis (cutoff date: 30 June 2022) of iCREST-CD to mainly evaluate the indication and outcomes of initial biologic therapy.
Methods
Patients newly diagnosed with CD after June 2016 based on the diagnostic criteria of the Japanese Guidelines, aged ≥16 years at the time of informed consent with no prior exposure to biologics were enrolled. Patient demographics, clinical data, disease activity and medical treatment were recorded. Biologic use without prior steroid use was defined as top-down and biologic use with prior steroid use was defined as step-up.
Results
A total of 672 eligible patients (68.2% male) with mean age (±SD) of 29.4 (13.1) years were analysed. Cumulative proportion of patients prescribed 5-aminosalicylic acid, steroids, immunomodulators, and biologics at 6- and 12-months from diagnosis were 71.3%, 40.6%, 31.4%, and 47.5%; and 75.0%, 43.6%, 36.0%, and 59.7%, respectively (Figure 1).
A total of 498 patients received biological therapy—infliximab (IFX; 121 24.3%), adalimumab (ADA; 244 49.0%), ustekinumab (UST; 107 21.5%), and vedolizumab (VDZ; 26 5.2%). The mean age (±SD) at the initiation of biologic treatment was IFX: 28.2 (11.3), ADA: 26.6 (10.8), UST: 30.4 (14.1), and VDZ: 36.2 (17.4), and the mean (±SD) levels of C-reactive protein (CRP) (mg/L) was IFX: 25.9 (26.8), ADA: 18.9 (26.0), UST: 13.5 (17.9), and VDZ: 9.5 (19.0) (Table.1). The initial biologic treatment persistence rates of IFX, ADA, UST and VDZ at 36-months were 77.5%, 75.8%, 79.8%, and 49.0%, respectively (Figure 2).
Patients receiving top-down and step-up therapy were 284 (57.0%) and 214 (43.0%), respectively. The treatment persistence rate of initial biologics by top-down and step-up therapy at 36-months from diagnosis was 81.6% and 66.9%, respectively (P=0.001) (Figure 3).
Conclusion
This registry study that demonstrated the treatment persistence rate of initial biologic therapy was significantly higher in the top-down than the step-up approach.
Abstract
Background
Previous reports showed that disease activity before treatment affected long-term continuation of anti-tumour necrosis factor (anti-TNF) therapy in patients with Crohn’s disease ...(CD). However, there is no consensus about which anti-TNF agent should be selected dependent on patient’s condition. The aim of this study was to investigate factors affecting the continuation period of anti-TNF therapy and to clarify how to select each anti-TNF agent in patients with CD.
Methods
This was a retrospective multicenter cohort study of consecutive patients who started anti-TNF therapy (infliximab: IFX or adalimumab: ADA) as an induction therapy from January 2010 to March 2019 at 16 hospitals participating in the Osaka Gut Forum. We excluded patients who did not respond to therapy or had toxic events within 8 weeks. Factors affecting the continuation period of each anti-TNF agent such as backgrounds, blood tests, clinical features before treatment and concomitant medications were analyzed by the Cox proportional hazards model. The cumulative continuation rate of each agent was analyzed by the Kaplan–Meier method and evaluated by log-rank test.
Results
A total of 250 patients were enrolled (IFX /ADA; 138 /148 treatments, bio-naïve; 73%, median age; 36 years Interquartile range (IQR); 24–46, median disease duration; 2.0 years 0.0–11.0, median observation period; 4.5 years 3.9–5.0). Median Harvey–Bradshaw Index (HBI), C-reactive protein (CRP) and Albumin (Alb) were 5 3–8, 0.71 mg/dl 0.14–2.04 and 3.5 g/dl 3.0–4.0, respectively. In patients with Alb ≥3.5 g/dl before treatment (median value), patients treated with IFX showed no significantly higher continuation rate than those with ADA. However, in those with Alb <3.5 g/dl, patients treated with IFX (N =82) showed significantly higher continuation rate than those with ADA (N = 50) (p = 0.007). In the observation period, 50%/34% of patients treated with IFX /ADA increased dose and 29% /38% of them concomitantly used azathioprine. In patients with Alb <3.5g/dl, by univariate analysis, stricturing and penetrating disease (B2 and B3/B1) hazard ratio (HR); 4.18, 95% Confidence interval (CI); 1.83–12.0, disease duration HR; 3.57, 95% CI; 1.16–9.77, and IFX/ADA HR; 0.48, 95% CI; 0.28–0.83 were extracted as factors affecting continuation period of anti-TNF therapy. Furthermore, B2 and B3/B1 HR; 3.80, 95% CI; 1.60–11.2 and IFX /ADA HR; 0.49, 95% CI; 0.26–0.92 were extracted by multivariate analysis. After 8 weeks after treatment, the increase in Alb level was significantly higher in patients with IFX than those with ADA (p = 0.006), although there was no difference in HBI and CRP.
Conclusion
When serum Alb level is less than 3.5 g/dl before treatment, IFX can be used longer than ADA for CD patients.
Abstract
Background
Immune responses to the SARS-CoV-2 vaccination may be influenced by immunomodulatory drugs (IMDs). We investigated the immune responses and safety in fully vaccinated Japanese ...patients with IBD.
Methods
IBD patients and control subjects at 39 institutes were invited to participate in the study from March to October 2021. Blood sample collections to measure anti-SARS-CoV-2 spike IgG antibody titers were planned pre-1st vaccination, pre-2nd vaccination, and at 4 weeks, 3 months and 6 months post-2nd vaccination. Immune responses were compared between groups, considering baseline characteristics and IMD treatments. (UMIN000043545) The interim analyses presented here include mainly data from the 4-weeks post-2nd vaccination time-point.
Results
In total, 679 IBD patients and 203 controls were enrolled (Table 1). The IBD group received the BNT162b2 vaccine (86.2%) and the mRNA-1273 vaccine (12.5%), and the control group received the BNT162b2 vaccine (86.9%) and the mRNA-1273 vaccine (12.1%). Only 4 cases (0.7%) in the IBD group and 2 (1.0%) in the control group were infected with COVID-19. Adverse events of 2nd vaccination occurred in 48.4% of the IBD group and 35.1% of the control group. Comparison between administrated and non-administrated IBD patients for each IMD revealed an attenuated genomic mean titer (GMT U/mL) in those taking systemic steroids (18.85 vs 31.24), anti-TNF monotherapy (28.31 vs 42.99), anti-TNF therapy+ immunomodulator (IM) (12.86 vs 35.26), vedolizumab+IM (19.49 vs 30.39), ustekinumab+IM (20.44 vs 30.79), and tofacitinib (9.54 vs 32.08), but not in those taking oral 5-ASA (29.50 vs 32.40), or vedolizumab (41.85 vs 40.20) and ustekinumab (55.56 vs 39.26) monotherapies. Estimated least square means of the GMT by a multiple linear regression model are shown in Table 2. GMTs were significantly influenced by increasing age and allergy (51.2, 95%CI 42.1–62.3; p=0.0293), and tended to be influenced by COVID-19 infection (139.1, 41.0–472.2; p=0.0572). Sex, smoking, drinking, IBD, and adverse events of 2nd vaccination did not affect the GMT. The GMT was significantly higher for mRNA-1273 (90.3 60.8–134.1) than for BNT162b2 (39.6 35.2–44.6, p= 0.0001). Systemic steroids (22.9 13.9–37.7, p=0.0119), IM (24.2 18.7–31.4, p<0.0001), anti-TNF agents (20.8 15.3–28.3, p<0.0001), vedolizumab (25.2 15.0–42.2, p=0.0409), ustekinumab (28.9 18.5–45.0, p=0.0754), and tofacitinib (5.5 2.8–10.9, p<0.0001), but not oral 5-ASA (39.1 31.9–47.9, p=0.3225), attenuated GMTs at 4 weeks post-2nd vaccination (Table 2).
Conclusion
Aging and most IMD options attenuated immunogenicity in fully vaccinated IBD patients. Prioritization of a booster vaccination should be considered for IBD patients treated with IMDs.
Abstract
Background
Information on patient demographics and disease characteristics at the time of Crohn’s disease (CD) diagnosis is considered to be an important aspect in the treatment and ...management of CD. However, reports on phenotypes, disease course, and treatment impact in newly diagnosed CD patients are limited. An interim analysis of a large registry study was conducted to analyze the clinical characteristics of CD patients at the time of diagnosis.
Methods
This prospective, non-interventional, observational registry study was conducted at 19 tertiary centers for CD treatment in Japan. Patients newly diagnosed with CD after Jun 2016 based on diagnostic criteria of the Ministry of Health, Labour & Welfare of Japan (age ≥16 years (yrs) at the time of informed consent with no prior exposure to biologics) were enrolled. Patient demographics, diagnostic procedures and categories, disease location and behavior of the lesions (based on Montreal classification) at time of CD diagnosis, were recorded.
Results
Patients were enrolled between Dec 17, 2018 and Jun 30, 2020, and a total of 672 eligible patients were analyzed; 93.3% (n=627) had definitive diagnosis and 68.2% were men. At the time of diagnosis, median age was 25 (range 13–86) yrs, and peak disease onset was 20–24 yrs. Diagnostic imaging examinations included conventional ileocolonoscopy (542/665, 81.5%), esophagogastroduodenoscopy (413/665, 62.1%), small bowel capsule endoscopy (74/665, 11.1%), balloon-assisted enteroscopy (149/665, 22.4%), CT enterography (74/665, 11.1%), and MR enterography (45/665, 6.8%). Most common disease location was L3 (ileocolonic), followed by, L1 (ileal) and L2 (colonic), 60.1%, 22.7%, and 16.3% of 664, respectively.
Nonstricturing/nonpenetrating disease (B1) was most common behavior, followed by stricturing (B2) and penetrating disease (B3), 62.8%, 25.8% and 10.7% of 662, respectively; perianal disease was seen in 48.9% of 662.
Interestingly, disease phenotype was different between the different age-at-onset groups (A1 ≤16 yrs, A2 17–39 yrs, A3 40–64 yrs, and elderly defined by age of onset ≥65 yrs; Figure 1–3). The male-to-female ratios were also different between these groups (A1: 1.7, A2: 2.6, A3: 1.3 and elderly: 1.3).
Conclusion
The study provides novel prospective insight on the clinical characteristics of newly diagnosed CD patients. Disease phenotype varied between patients <40 yrs and those ≥40 yrs of age in terms of male-to-female ratios, disease location/disease behavior/presence or absence of perianal lesion at the time of diagnosis. The ongoing prospective follow-up will provide additional insight.
Heat-shock proteins (HSPs) act as molecular chaperones binding endogenous antigenic peptides and transporting them to major histocompatibility complexes. HSPs chaperone a broad repertoire of ...endogenous peptides including tumor antigens. For the immunotherapy of tumors, a strategy using HSPs may be more advantageous than other procedures because the identification of each tumor-specific antigen is not necessary. In this study, the efficacy of immunotherapy against minimal residual leukemia cells using HSP preparations was evaluated. HSP70 and GP96 were purified from syngeneic leukemia cell line A20 and immunized into BALB/c mice during the reconstitution period of the immune system after syngeneic bone marrow transplantation. In this procedure, all mice not immunized were dead within 60 days of A20 inoculation, whereas the survival times of HSP-immunized mice were significantly prolonged. In addition, the depletion of either CD4+ or CD8+ T lymphocyte significantly abrogated this efficacy, indicating that both CD4+ and CD8+ T lymphocytes were required for tumor cell rejection. Moreover, the vaccination of HSPs elicited a specific response of potent CD8+ T lymphocytes cytotoxic against A20 in vitro. These observations suggest that immunization of the complex of HSPs and peptides derived from leukemia cells leads to immune responses. These immune responses are sufficient to reject minimal amounts of leukemia cells for relatively immunocompromised mice after syngeneic bone marrow transplantation.
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