Patients In Clinical Remission Research Articles

Super-responder and clinical remission in patients with asthma on treatment with single biologic therapy or cycling therapy using dupilumab in a real-world setting.

Regarding the therapeutic target in asthma, super-responder status (SR) is a status without systemic corticosteroids. Recently, clinical remission (CR), being a status of prolonged absence of asthma symptoms without systemic corticosteroids and/or normal pulmonary function, has gained attention as a new therapeutic target in asthma. Here, we examined the percentage and features of asthma patients on treatment with dupilumab showing SR and CR. 49 asthma patients used subcutaneous dupilumab for >1 year between April 2019 and November 2022. The status of SR and CR for 1 year was evaluated. Patients without any maintenance oral corticosteroids and exacerbations requiring systemic corticosteroids were classified as SR. CR was defined using three definitions based on changes in asthma symptoms and pulmonary function in addition to achieving SR for 1 year: CR without pulmonary function criteria (CR w/o F), fulfilment of asthma symptom improvement (asthma control questionnaire score <0.75 or asthma control test score ≥23); and CR-70 or CR-80, pulmonary function improvement (%forced expiratory volume in 1 second ≥70% or ≥80%) in addition to achieving CR w/o F, respectively. 38 (77.6%), 22 (44.9%), 13 (26.5%), 12 (24.5%) of patients had SR, CR w/o F, CR-70, and CR-80, respectively. Severe eosinophilic chronic rhinosinusitis was significantly more found in patients with SR and CR based on all three definitions than in those without. This study identified the percentage and features of patients on treatment with dupilumab showing SR and CR in a real-world setting. The outcome beyond CR on biologic treatment should be clarified.

P600 Efficacy of different modalities of faecal microbiota transplantation to induce clinical remission in patients with ulcerative colitis: a systematic review and network meta-analysis

Abstract Background We aimed to compare the efficacy of different modalities of faecal microbiota transplantation (FMT) to induce clinical remission in patients with ulcerative colitis (UC). Methods We performed a systematic review and network analysis (random effects model) of randomized controlled trials including at least one arm of FMT in adult patients with active UC. Primary endpoint, i.e. clinical remission (total Mayo score≤ 2 with Mayo endoscopic score≤ 1), was assessed between week 6 and 12. Results are expressed as relative risk with 95% confidence intervals, adjusted for bowel cleansing and pre-FMT antibiotics therapy. Ranking of FMT modalities for clinical remission was calculated as their surface under the cumulative ranking (SUCRA), which represents the percentage of efficacy achieved by an agent compared with an imaginary agent that is always the best without uncertainty. Heterogeneity among studies was evaluated by τ² (global statistical heterogeneity across all comparisons). Results Among the 12 selected studies, patients were exclusively bio-naïve in 4 studies (4/12), while between 9 and 32% had prior biologics exposure in the other trials. Risk of bias was low across all domains in 7 studies. Global heterogeneity was negligible (τ² = 0). After adjustment on bowel cleansing and pre-FMT antibiotics, oral capsule (RR=7.1[1.8-33.3]), lower GI FMT (RR=4.5[1.7-12.5] and combination of both (RR=12.5[2.1-100]) were more effective than placebo to induce clinical remission contrary to upper GI FMT (RR=1.1[0.2-7.7]) and autologous FMT (RR = 0.8[0.2-3.8](Table 1). The combination of lower GI FMT and oral capsule was significantly more effective than upper GI FMT to induce clinical remission (RR=10.7[1.1-104.2]). Combination of lower GI FMT and oral capsule ranked highest for the induction of clinical remission (SUCRA=0.93), followed by oral capsule (SUCRA=0.82) and lower GI FMT (SUCRA=0.72). Autologous FMT ranked lower than placebo (SUCRA=0.12vs0.22). We performed a sensitivity analysis distinguishing single donor FMT and multi-donor FMT (pooled samples from different donors). Combination of lower GI FMT and oral capsule ranked highest for the induction of clinical remission (SUCRA=0.89), followed by single donor lower GI FMT (SUCRA=0.70), multi-donor (pooled samples) lower GI FMT (SUCRA=0.65), multi-donor (pooled samples) oral capsule (SUCRA=0.61), single donor oral capsule (SUCRA=0.60). Conclusion In this network meta-analysis, we confirmed the efficacy of FMT to induce clinical remission in patients with UC. The combination of lower GI and oral capsule FMT seems to be the best modality of FMT for patients with UC while upper GI FMT is not suitable. In clinical trials, autologous FMT should be avoided due to a potential detrimental effect.

P386 Persistence of bowel urgency despite clinical remission after induction therapy is associated with unfavorable long-term outcomes in patients with ulcerative colitis: results from the multicenter UC-RGENCY study

Abstract Background STRIDE 2 recommendations define clinical remission as no rectal bleeding and normalization of stool frequency in patients with ulcerative colitis (UC), without including bowel urgency (BU) despite its negative impact on quality of life. In this large multicenter cohort, we aimed to assess whether the persistence of BU after induction therapy is independently associated with poor long-term outcomes in patients with UC. Methods From a multicenter retrospective study, we included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) &amp;gt; 2, who started biologics or small molecules between Jan2019 and June2022. BU was defined as a binary criterion based on the SCCAI definition. The primary endpoint was the time to drug discontinuation due to active UC. Secondary endpoints were time to relapse, time to colectomy as well as steroid-free clinical remission (pMS ≤ 2) (CFREM), endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and mucosal healing (CFREM + MES ≤ 1 + histological remission i.e. Nancy index ≤ 1) at last follow-up. Results Among 473 patients with UC, 270 were assessed for BU after induction therapy (week 16) (mean age 43.0±17.0 years-old, median UC duration 6 [3-11] years, female gender=54.0%, pancolitis=45.9%). The median follow-up was 14 [8-22] months. The rate of CFREM after induction therapy was 54.4% (147/270) while 21.5% (58/270) had remaining bowel urgencies after induction therapy. Among the 147 patients achieving remission after induction therapy, 12 had persistent BU (8.2%), while 62.6% (77/123) of patients with no CFREM after induction therapy did not have any BU. The agreements between BU and rectal bleeding (75.2%, κ-coefficient = 0.33±0.06) or normalization of stools frequency (67.9%,κ-coefficient = 0.35±0.05) were mild. Among the patients with persistent BU after induction therapy, only 3.7% had no endoscopic activity (MES = 0). In multivariable analyses including CFREM at week 16, persistence of BU after induction therapy was independently associated with the time to drug discontinuation (HR=2.0[1.1-3.5], p=0.016) and colectomy (HR=4.4[2.3-8.4], p&amp;lt;0.001), and absence of mucosal healing (OR = 5.0[1.1-24.8], p=0.046) at last follow-up. A trend was also observed regarding the association between remaining BU after induction therapy and no CFREM (OR=6.1[0.8-48.0], p=0.085) or absence of endoscopic remission (OR=2.4[0.9-6.1], p=0.077) at last follow-up. Conclusion Persistence of BU despite clinical remission is associated with higher risk of drug discontinuation due to active UC, colectomy and lower likelihood of mucosal healing. Bowel urgency should be implemented into international guidelines to define clinical remission in patients with UC.

P569 Persistence and safety of upadacitinib in Crohn’s disease and ulcerative colitis in real life: results from a Spanish nationwide study

Abstract Background Upadacitinib (UPA) has demonstrated its efficacy in patients with inflammatory bowel disease (IBD) in clinical trials. However, these results may differ from those achieved in clinical practice. Thus, persistence and safety should be analysed in a real-world scenario. Main aim: to evaluate the persistence of UPA in real life, both in Crohn’s disease (CD) and ulcerative colitis (UC). Secondary aims: to assess the effectiveness and safety of UPA. Methods Multicentre, retrospective study of IBD patients who received UPA for IBD in clinical practice. Persistence was calculated from the date of the first dose to the date of the last dose of UPA. For effectiveness assessment, only patients with active IBD at baseline were considered. Active disease was defined as Harvey-Bradshaw index &amp;gt;4 in CD, and partial Mayo score &amp;gt;2 in UC. Negative imputation method was used to deal with missing data. Cox regression and logistic regression analyses were used to identify predictive factors of treatment persistence and effectiveness, respectively. Results One hundred patients from 34 centres were included, 68 with CD and 32 with UC. All patients had been previously exposed to biologics (median 4, IQR 3-4), and 26% to JAK inhibitors (78% in UC); 37% of them were on steroids at baseline. Regarding UPA survival, 81% of patients remained on UPA at month 6, and 66% at month 12 (figure 1). Loss of response was observed in 34% per patient-year of follow-up. Dose intensification was required in 18%, 72% of whom responded clinically. Finally, 23 patients interrupted UPA during the follow-up. Age below 40 at UPA start and CD were associated with higher risk of UPA withdrawal (HR 2.4; 95%CI:1.0-5.7 and HR 3.7; 95%CI:1.0-12.9, respectively). Seventy-eight patients had active disease at baseline and were considered for the effectiveness analysis. Short-term clinical remission was achieved in 51%, 59% and 64% at week 4, 8 and 12; focusing on the type of IBD, clinical remission was achieved in 79% of UC vs. 54% of CD (p=0.03) at week 12. In the long-term, 53% and 42% remained in clinical remission at months 6 and 12. Clinical remission in patients exposed to JAK inhibitors was achieved in 75% and 79% at week 8 and 12, respectively; and in the long-term, in 54% and 55% at months 6 and 12. A total of 41 patients (41%) presented at least one adverse event (Table 1). Conclusion In the largest real-life cohort of IBD patients treated with UPA, the proportion of patients maintaining UPA at 12 months seems relatively high, regardless of prior exposure to JAK inhibitors. UPA seems to be effective in inducing and maintaining clinical remission, both in CD and in UC. The safety profile was similar to that previously described.

P1084 Persistence and efficacy of Ustekinumab in Crohn's disease after antiTNF failure. May the response of the second biologic therapy be better than the first one?

Abstract Background After antiTNF failure, a second antiTNF in Crohn's disease (CD) is effective to achieve and maintain remission, but only50% remain with the drug after 12 months of treatment. Ustekinumab (UST) has a better persistence as second-line treatment and is effective to induce and maintain long-term remission. Methods Retrospective and observational study retrieved from a prospective database of Crohn's disease patients treated with UST, after approval of Research Ethics Committee. Data were collected at the beginning of treatment and after 4, 8, 16, 24 weeks, 12, 24, 36, 48, 60 months and at the end of follow-up (UST discontinuation or March 2023 if treatment continues). Primary Objective evaluate the persistence with UST and clinical (Harvey-Bradshaw index (HBI)&amp;lt;4) and biological remission (C-reactive protein (CRP)&amp;lt;5 mg/dl and/or fecal calprotectin (FC)&amp;lt;250 mg/kg) in each period of follow up. Clinical remission in perianal disease was defined as absence of drainage both spontaneous and after soft pressure. Persistence of the first biologic therapy, reasons of treatment change, dose optimization, surgery, hospitalizations and adverse events were also evaluated. Results 68 patients were included (Table 1). Median survival of antiTNF is 1.65 years (IC95% 1.18-2.56). 72.06% patients receive antiTNF 1 year, 45.59% 2 years, 30.88% 3 years and only 8.82% are treated during 10 years. Persistence with UST was longer than with antiTNF. 93.2% of patients receive UST 1 year, 89.4% 2 years and 86.1% 3 years. There was a significant reduction of fecal calprotectin values during follow-up (p=0.0002). 7 patients with perianal disease achieved clinical remission (70.00%) and 4 complete fistula healing in magnetic resonance enterography (40.00%) at the end of follow-up. 60.29% patients received 90 mg every 8 weeks, but 36.76% required dose optimization (23.50% 90mg sq/4 weeks and 13.24%130mg/4 weeks ev). 86.76% continue UST at the end of follow-up, with a mean duration of treatment of 27.65 months (SD 18.27). 9 patients (13.24%) stopped treatment (1 primary non response, 5 loss of response, 3 adverse events). 11 patients (16.18%) needed surgery and hospitalization during follow up; 63.60% of them had stricturing disease. Conclusion Persistence with UST as a second line therapy was superior to antiTNF in first-line. 86.76% continued treatment with UST after 2 years. UST achieved early and long-term clinical remission in approximately two thirds of patients. 36.76% of patients required dose optimization. UST was effective in perianal disease after antiTNF failure. Figure 1 shows clinical remission in patients with basal HBI&amp;gt;4.

P973 Real-world data on the effectiveness on IBD of anti-IL23 drugs prescribed for psoriasis indication

Abstract Background There is a significant association between psoriasis and IBD, which share the pathogenic role of IL-23. In the dermatological field, drugs targeting the p19 subunit of IL-23, such as risankizumab, guselkumab, and tildrakizumab, have been approved for the treatment of moderate to severe psoriasis. However, there are still no real-life data on the efficacy and safety profile of IL-23 inhibitors in patients with IBD. Methods A prospective, single center observational study was conducted on patients with IBD and psoriasis from April 2021 to March 2023 at the gastroenterological-dermatological outpatient clinic at “Città della Salute e della Scienza of Turin”, Italy. Patients received a dermatological indication to start drug therapy with IL-23 inhibitors according to the dermatological dosing schedule. They were treated either with guselkumab subcutaneously at a dose of 100 mg every 8 weeks, or with risankizumab subcutaneously at a dose of 150 mg every 12 weeks, or with tildrakizumab 100 mg every 12 weeks subcutaneously. Objectives of this study included evaluating the achievement of clinical remission at 3, 6, and 12 months, defined as disease activity with Harvey-Bradshaw Index (HBI) &amp;lt; of 5 in CD and pMAYO &amp;lt; of 2 in UC. Results At 3 months after the start of drug treatment, clinical remission was achieved by 73.3% of patients (p=0.006). This number also remained almost constant at 6 (62.4%, p=0.008) and 12 months (60.3%, p=0.04). In addition, there was a statistically superior steroid-free clinical remission compared to T0 at 3 (15.3% vs 73.3%, p=0.006) and 6 months (7.1% vs 54.1%, p=0.04). No major side effects were reported. Two cases of arthralgias (11.8%) and one case of fever with chills (5.9%) were reported. IL-23 inhibitors appear to be effective in maintaining the steroid-free clinical remission. In addition, there was a reduction in fecal calprotectin values to a median value at 6 months of 81.0 (95%IC= 28.2-249.8; p=0.03) from a median value at T0 of 343.1 (95%IC= 44.8-869.7). The maintenance rate of IL-23 inhibitors therapy at the end of follow-up was 75.8%. Conclusion In this study risankizumab, guselkumab, and tildrakizumab appear to be effective in inducing clinical remission and steroid-free clinical remission in patients with IBD. In addition, they appear to be effective in maintaining steroid-free clinical remission. IL-23 inhibitors demonstrated a good safety profile in patients with IBD. Despite the limitations of the study with the need to publish further real-world data on a larger scale and with higher dosing of IL-23 inhibitors, the results obtained are promising as they, for the first time, provide real-life support for the clinical potential of these drugs as treatment for IBD in addition to psoriasis.

Coconut Water Induces Clinical Remission in Mild to Moderate Ulcerative Colitis: Double-blind Placebo-controlled Trial

Background and AimsCoconut water is anti-inflammatory, can manipulate the gut microbiome and is a rich source of potassium. Gut microbiome modulation improves outcomes in UC, and potassium possesses in vitro anti-inflammatory property. We evaluated the effect of coconut water as an adjunct therapy for patients with mild-moderate UC. MethodsThis single-center double-blind placebo-controlled trial randomized patients with mild-moderate(simple clinical colitis activity index-SCCAI:3–9) endoscopically active UC(ulcerative colitis endoscopic index of severity-UCEIS>1) in 1:1 ratio to coconut water + standard medical therapy-SMT(CW) vs placebo + SMT. 400ml of coconut water was administered for 8weeks. Primary outcome measure was clinical remission(SCCAI ≤2) and secondary outcome measures were clinical response(SCCAI decline ≥3) and adverse events at 8weeks. Microbiome was analyzed at baseline and 8weeks. ResultsOf 121 patients screened, 95 were included for modified intention to treat analysis(49-CW, 46-placebo)[mean age-37.2±11.2years; males-54.1%; disease duration-48(IQR:24–90)months; pancolitis-26.1%; SCCAI-5(IQR:4 – 6); UCEIS-4(IQR:3 – 5)]. Clinical response[57.1% vs 28.3%, p=0.01, OR-3.4(95%CI:1.4 – 7.9)], remission[53.1% vs 28.3%, p=0.02, OR-2.9(95%CI:1.2 – 6.7)] and proportion of patients with fecal calprotectin(FCP)<150μg/g[30.6% vs 6.5%, p=0.003, OR-6.3(95%CI:1.7 – 23.6)] were significantly higher in CW. The relative abundance of bacterial taxa which had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP, increased at 8weeks in CW, and this effect was independent of disease activity and dietary fiber. Adverse events were comparable and no patient developed hyperkalemia. ConclusionCoconut water was more effective than placebo for induction of clinical remission in patients with mild to moderate UC.The trial was prospectively registered on clinical trials registry India (No: CTRI/2019/03/01827)

Clinical Remission in Patients Affected by Severe Eosinophilic Asthma on Dupilumab Therapy: A Long-Term Real-Life Study.

Background. Nowadays, highly selective biological drugs offer the possibility of treating severe type 2 asthma. However, in the real-life setting, it is crucial to confirm the validity of the chosen biological treatment by evaluating the achievement of clinical remission. Study purpose. The main aims of this real-life study were to evaluate the efficacy of dupilumab in terms of clinical, functional, and inflammatory outcomes at 6, 12, 18, and 24 months of treatment and to estimate the percentage of patients achieving partial or complete clinical remission at 12 and 24 months of treatment. In addition, we attempted to identify whether baseline clinical characteristics of patients could be associated with clinical remission at 24 months of treatment. Materials and methods. In this observational prospective study, 20 outpatients with severe uncontrolled eosinophilic asthma were prescribed dupilumab and followed-up after 6, 12, 18, and 24 months of treatment. At each patient visit, the need for oral corticosteroids (OCS) and corticosteroid required dose, number of exacerbations during the previous year or from the previous visit, asthma control test (ACT) score, pre-bronchodilator forced expiratory volume in the 1st second (FEV1), fractional exhaled nitric oxide at a flow rate of 50 mL/s (FeNO50), and blood eosinophil count were assessed. Results. The number of OCS-dependent patients was reduced from 10 (50%) at baseline to 5 (25%) at one year (T12) and 2 years (T24). The average dose of OCS required by patients demonstrated a significant reduction at T12 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.015), remaining significant even at T24 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.016). The number of exacerbators showed a statistically significant decrease at T24 (10 patients, 50% vs. 3 patients, 15%, p = 0.03). The mean number of exacerbations demonstrated a statistically significant reduction at T24 (1.45 ± 1.58 vs. 0.25 ± 0.43, p = 0.02). The ACT score improved in a statistically significant manner at T12 (15.30 ± 4.16 vs. 21.40 ± 2.35, p < 0.0001), improving further at T24 (15.30 ± 4.16 vs. 22.10 ± 2.59, p < 0.0001). The improvement in pre-bronchodilator FEV1 values reached statistical significance at T24 (79.5 ± 14.4 vs. 87.7 ± 13.8, p = 0.03). The reduction in flow at the level of the small airways (FEF25-75%) also demonstrated an improvement, although it did not reach statistical significance either at T12 or T24. A total of 11 patients (55%) showed clinical remission at T12 (6 complete + 5 partial) and 12 patients (60%) reached clinical remission at T24 (9 complete + 3 partial). Only obesity was associated with a negative odds ratio (OR) for achieving clinical remission at T24 (OR: 0.03, 95% CI: 0.002-0.41, p = 0.004). No other statistically significant differences in baseline characteristics emerged between patients who reached clinical remission at T24 and the group of patients who did not achieve this outcome. Conclusion. Dupilumab appears to be an effective drug in promoting achievement of clinical remission in patients with severe uncontrolled eosinophilic asthma. The achievement of clinical remission should be continuously evaluated during treatment. Further studies are needed to clarify whether certain baseline clinical characteristics can help predict dupilumab favorable outcomes.

Relief of Airflow Limitation and Airway Inflammation by Endoscopic Sinus Surgery in a Patient with Severe Asthma with Eosinophilic Chronic Rhinosinusitis.

Although endoscopic sinus surgery (ESS) is beneficial in improving asthma symptoms, its impact on the lung function in patients with asthma and chronic rhinosinusitis remains unclear. We herein report a case of severe asthma with eosinophilic chronic rhinosinusitis, in which ESS substantially improved airflow limitation and concomitantly reduced fractional exhaled nitric oxide and blood eosinophil counts. ESS likely relieved airflow limitation by suppressing type 2 inflammatory pathways. This case highlights ESS as a promising strategy for achieving clinical remission in patients with severe asthma and chronic rhinosinusitis.

Ultrasound versus clinical remission in patients with early rheumatoid arthritis: concordance and relationship with therapy discontinuation.

To evaluate prevalence of ultrasonographic remission (USR) and concordance with clinical remission in "drug-free" or "on-treatment" patients with early rheumatoid arthritis (RA). We carried out a cross-sectional study including consecutive early RA patients in SDAI remission ≥6 months in the period 06/2022 to 02/2023. CDAI, DAS28, DAS44 and Boolean remission were also evaluated. Patients underwent B-mode and Power Doppler (PD) assessments of 42 joints and 20 tendons. Synovitis, tenosynovitis and PD were graded semi-quantitatively (0-3) using standardised scores. Four definitions of USR were examined: USR1: absence of synovial hypertrophy (SH) and PD; USR2: SH≤1 and PD=0; USR3: SH≤1 and PD≤1; USR4: PD negative. Eighty patients were enrolled, of whom 12 drug-free. Overall remission rates were 100.0%, 83.7%, 91.2%, 96.2% and 80.0% for SDAI, CDIA, DAS28, DAS44 and ACR/EULAR Boolean criteria, respectively. 100% of drug-free patients were in remission according to all indices. The rate of USR in drug-free versus on-treatment remission was 58.3%, 66.7%, 66.7%, 83.3% versus 70.6%, 85.3%, 88.2%, 91.2% for USR1, USR2, USR3 and USR4, respectively. While clinical remission seems more frequent in drug-free patients, USR is more often observed on-treatment.

Molecular profiling of clinical remission in psoriatic arthritis reveals dysregulation of FOS and CCDC50 genes: a gene expression study.

In psoriatic arthritis (PsA), the primary goal of treatment is clinical remission. This study aimed to characterize the molecular profile underlying the induced clinical remission in patients with PsA, comparing the remission state and the healthy condition. Whole blood transcriptomic analysis was performed on groups of 14 PsA patients in TNFi-induced clinical remission (DAPSA ≤ 4), 14 PsA patients with active disease (DAPSA > 14), and 14 healthy controls (HCs). Then, all differentially expressed genes (DEGs) derived from remission vs. HC comparison were analyzed for functional and biological characteristics by bioinformatics software. The gene expression of 12 genes was then validated by RT-qPCR in an extended cohort of 39 patients in clinical remission, 40 with active disease, and 40 HCs. The transcriptomic analysis of PsA remission vs. HCs highlighted the presence of 125 DEGs, and out of these genes, 24 were coding genes and showed a great involvement in immune system processes and a functional network with significant interactions. The RT-qPCR validation confirming the down- and upregulation of FOS (FC -2.0; p 0.005) and CCDC50 (FC +1.5; p 0.005) genes, respectively, in line with their role in orchestrating inflammation and bone metabolism processes, may be related to PsA pathophysiology. The transcriptomic profile of clinical remission in PsA is similar to a healthy condition, but not identical, differing for the expression of FOS and CCDC50 genes, which appears to play a key role in its achievement.

Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients

Allogeneic invariant natural killer Tcells (allo-iNKTs) induce clinical remission in patients with otherwise incurable cancers and COVID-19-related acute respiratory failure. However, their functionality is inconsistent among individuals, and they become rapidly undetectable after infusion, raising concerns over rejection and limited therapeutic potential. We validate a strategy to promote allo-iNKT persistence in dogs, an established large-animal model for novel cellular therapies. We identify donor-specific iNKT biomarkers of survival and sustained functionality, conserved in dogs and humans and retained upon chimeric antigen receptor engineering. We reason that infusing optimal allo-iNKTs enriched in these biomarkers will prolong their persistence without requiring MHC ablation, high-intensity chemotherapy, or cytokine supplementation. Optimal allo-iNKTs transferred into MHC-mismatched dogs remain detectable for at least 78days, exhibiting sustained immunomodulatory effects. Our canine model will accelerate biomarker discovery of optimal allo-iNKT products, furthering application of MHC-unedited allo-iNKTs as a readily accessible universal platform to treat incurable conditions worldwide.

Expression of Circulating let-7e and miR-126 May Predict Clinical Remission in Patients With Crohn's Disease Treated With Anti-TNF-α Biologics.

The identification of new biomarkers predictive of response to antitumor necrosis factor alpha (anti-TNF-α) monoclonal antibodies remains an unmet medical need in Crohn's disease (CD) because a high percentage of patients show no clinical improvement after treatment or can lose response over time. MicroRNAs (miRNAs) can regulate inflammatory and immunological responses and were found to play a role in CD. Baseline serum samples from 37 CD patients previously treated with infliximab or adalimumab, as per clinical practice, were obtained from the serum library at the Gastroenterology Unit of the University Hospital of Pisa, Italy. Patients were categorized as responders or nonresponders based on the following treatment outcomes: clinical remission at weeks 14 and 54 and endoscopic remission at week 54. The expression levels of a panel of selected miRNAs were analyzed by real-time polymerase chain reaction. Comparisons of miRNA expression between responders and nonresponders and statistical analyses were performed by MedCalc and GraphPad Prism software. Receiver operating characteristic curve analyses were calculated to evaluate the predictive performance of potential biomarkers. Patients in clinical remission at week 14 had a lower let-7e expression, whereas those in clinical remission at week 54 had lower levels of circulating miR-126 than nonresponders. The receiver operating characteristic curve analysis identified optimal cutoff values with assay sensitivity and specificity of 92.9% and 61.1%, for let-7e, and 62.5% and 83.3%, for miR-126, respectively. These results provide evidence that expression levels of circulating let-7e and miR-126 at baseline may predict clinical remission in CD patients treated with anti-TNF-α biologics.

Primary Immune Thrombocytopenia and Thrombopoietin Receptor Agonists: Feasibilities of Treatment Discontinuation upon Achieving Stable Complete Platelet Response

Aim. To assess the stability of clinical remission in patients with primary immune thrombocytopenia (ITP) after withdrawal of thrombopoietin receptor agonists (TPO-RAs).&#x0D; Materials &amp; Methods. The study enrolled 456 patients with primary ITP who received second- and subsequent-line TPO-RA treatment. Complete platelet response (PR) was achieved in 338 patients, the therapy was discontinued in 116 of them. The present prospective clinical study started in 2014 and focused on the data of these 116 patients. Among them, there were 27 (23 %) men and 89 (77 %) women. By the time of TPO-RA therapy onset, the median age of the patients was 60 years (range 13–87 years), on ITP diagnosis date it was 52 years (range 1–80 years).&#x0D; Results. By the time of data analysis, 59 % of patients sustained PR after TPO-RA withdrawal. The median PR duration after TPO-RA withdrawal was 230 weeks. Romiplostim and eltrombopag recipients showed no significant differences in the survival rates without PR-loss after TPO-RA withdrawal. In the present study, the maximum PR duration achieved 9.5 years. The mid-term assessment of PR status was carried out in 3, 6, 12, 24, and 30 months after TPO-RA withdrawal and showed 99 %, 94 %, 83 %, 72 %, and 70 %, respectively. The number of previous therapy lines significantly affected the survival rates without PR-loss (p = 0.011). The age of patients, prior splenectomy, TPO-RA treatment duration, time to different PR levels on therapy, PR duration on TPO-RA therapy, and platelet count upon TPO-RA withdrawal showed no significant effect on this parameter. After PR-loss, TPO-RAs were administered again to 31 (27 %) patients. Repeated PR was achieved in 26 (84 %) of them.&#x0D; Conclusion. TPO-RA administration yields multi-year off-treatment remission in some patients with primary ITP. Upon therapy discontinuation, 59 % of patients with complete PR sustained PR for 3 months to 9.5 years. Stable PR after TPO-RA withdrawal significantly correlated with only one of the studied prognostic parameters, i.e., the number of previous therapy lines.

Long-term follow-up of the red density pilot trial: a basis for long-term prediction of sustained clinical remission in ulcerative colitis?

Red density (RD) technology is an automated operator-independent endoscopic scoring system for disease activity in ulcerative colitis (UC). In this retrospective analysis we aimed to assess the predictive value of the RD sore for sustained clinical remission. All 39 patients from the RD pilot trial were evaluated for clinical outcome in a 5-year period. The highest RD score was considered for Receiver operating characteristic (ROC) analysis to determine the cut-off of the RD for the composite endpoint of treatment failure (defined as mortality, colectomy, hospitalizations, flares and UC therapy changes). Statistical significance was considered P < 0.05. Reassessment of the RD score was possible in 36 patients. The composite endpoint was reached in 17 of 39 patients. ROC analysis for clinical remission showed a RD cut-off of 65, area under the ROC was 0.68, sensitivity of 0.71, and a specificity of 0.63. A RD score of ≥ 65 demonstrated a statistically non-significant increase in composite endpoint (hazard ratio 0.49 (95% confidence interval 0.1871-1.280); P = 0.1453). In conclusion, the RD score may be an independent predictor of clinical remission in patients with UC for the disease course up to 5 years, but results of the ongoing PROCEED-UC trial are to awaited for definite conclusions.

Severe asthma clinical remission after biologic treatment with anti-IL4/IL13: A real-life experience

IntroductionDupilumab, a fully human anti-interleukin-4/interleukin-13 monoclonal antibody, has shown efficacy in many aspects of Type-2 severe asthma management. Currently, we lack real-life studies addressing the achievment of clinical remission in patients treated with this biologic. Materials and methodsWe performed a prospective study enrolling 18 patients with severe asthma treated with Dupilumab. We assessed main clinical, functional and biological severe asthma features at baseline (T0) and after a 1-year course of treatment (T12). Clinical remission was defined at T12 in patients without asthma exacerbations, no oral corticosteroid (OCS) use, ACT ≥ 20 and FEV1 improvement ≥ 100 ml from baseline. ResultsAmong total population, 38.9% of patients achieved clinical remission at T12. Anti IL-4/IL-13 treatment significantly reduced asthma exacerbations and OCS use in the overall cohort, with a more pronounced ACT improvement in the remission group. Patients achieving clinical remission went through a step down of the inhalation therapy, suspending long-acting anti-muscarinics administration at T12. ConclusionsTreatment with anti-IL4/IL13 can induce clinical remission in patients with T2 severe asthma.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BackgroundMirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial.MethodsWe conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed.ResultsA total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer.ConclusionsMirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.)

Controlled Hookworm Infection for Medication-free Maintenance in Patients with Ulcerative Colitis: A Pilot, Double-blind, Randomized Control Trial.

Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC. Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection. At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang's blinding index 0.22; 95% CI, -0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL. A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible.

Mucosal Healing and Clinical Efficacy of Adalimumab in Small Intestinal Crohn's Disease (SIMCHA Study): Final Results From a Prospective, Open-Label, Single-Arm Study.

Endoscopic healing is a key treatment target in inflammatory bowel disease; few data are available on the clinical and endoscopic efficacy of biological therapy in upper gastrointestinal Crohn's disease. This study aimed to investigate small bowel mucosal healing and clinical efficacy of adalimumab therapy by video capsule endoscopy in patients with endoscopically active upper gastrointestinal Crohn's disease. This prospective, open-label, single-arm study included Crohn's disease patients with moderate-severe endoscopic proximal small bowel involvement, defined by a Lewis score >790. Patients were treated with adalimumab monotherapy for 24 weeks. Co-primary outcomes were endoscopic healing, defined as Lewis score <350, and endoscopic response, defined as >50% decrease in Lewis score. Secondary outcomes included clinical (Harvey-Bradshaw index <4) and biomarker remission (fecal calprotectin <250 μg/g, and C-reactive protein <5 mg/L). A total of 59 Crohn's disease patients were screened; 17 patients have met eligibility criteria and were enrolled. Endoscopic healing was observed in 8 patients (47.1%) and endoscopic response in additional 5 patients (29.4%) at 24 weeks. Median Lewis score was significantly decreased compared to baseline (1912 vs. 337, P = .0005). Eleven of 13 patients (84.6%) with clinical activity achieved clinical remission (baseline: 13/17 vs. week 24: 2/17, P < .0001). Nine of 10 patients with elevated C-reactive protein achieved normal C-reactive protein after treatment and the median C-reactive protein significantly decreased from 7.4 to 1.6 mg/L, P = .032. In contrast, no change was observed in fecal calprotectin pre- and posttreatment. Adalimumab induced endoscopic healing and clinical remission in patients with active small bowel Crohn's disease, with approximately half of the patients achieving endoscopic healing.

Repetitive administration of rituximab can achieve and maintain clinical remission in patients with MCD or FSGS

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients’ previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 (p<0.001) and 6 months (p<0.001). Relapse-free survival increased from 4.5 months (95%-CI 3–10 months) to 21 months (95%-CI 16–32 months) (p<0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.