scholarly journals Levels of Biosimilar Infliximab during and after Induction Treatment in Crohn’s Disease and Ulcerative Colitis—A Prospective Polish Population Study

2021 ◽  
Vol 10 (22) ◽  
pp. 5311
Author(s):  
Anna Pękala ◽  
Rafał Filip
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Induction Treatment ◽  
Therapeutic Drug ◽  
Induction Phase ◽  
Drug Levels ◽  
Trough Levels

Background: Primary lack or secondary loss of response to therapy with infliximab is a significant problem. This study aimed to evaluate the response to treatment in patients with Crohn’s disease (CD) and ulcerative colitis (UC) achieving therapeutic and sub-therapeutic trough levels of biosimilar infliximab (CT-P13). Results: A total of 65 patients (32 with CD and 33 with UC) were recruited. The overall response rate in both CD and UC patients exceeded 80%. There were no significant differences in treatment response and CT-P13 levels for patients with CD or UC. We did not find significant differences in the percentage of patients achieving drug levels of 3 μg/mL at week 6, 10, or 12; a significant decrease was observed at week 14. Up to 55.5% of patients with CD and 64.3% of patients with UC with sub-therapeutic CT-P13 levels at week 14 primarily responded to treatment. Conclusions: Intermediate measurements of drug levels at weeks 10 and 12 did not capture any pronounced decrease in infliximab concentrations below therapeutic levels in either group, thus suggesting no clinical usefulness. A significant percentage of patients primarily responded to treatment despite sub-therapeutic drug levels after the induction phase.

scholarly journals P414 Risk factors for the development of anti-drug antibodies to infliximab and adalimumab in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S378-S379
Author(s):  
E Khoo ◽  
A Lord ◽  
K Hanigan ◽  
A Croft ◽  
G Radford-Smith
Keyword(s):  
Risk Factors ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Lower Risk ◽  
Smoking Status ◽  
Drug Level ◽  
Enzyme Linked Immunosorbent Assay ◽  
Therapeutic Drug ◽  
Drug Levels ◽  
Low Serum

Abstract Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

scholarly journals A101 USTEKINUMAB LEVELS MEASURED DURING INDUCTION ARE ASSOCIATED WITH CLINICAL AND BIOCHEMICAL OUTCOMES AT WEEK 12 OF TREATMENT IN CROHN’S DISEASE

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 117-118
Author(s):  
M Walshe ◽  
K Borowski ◽  
K Boland ◽  
S Rho ◽  
J Stempak ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Negative Correlation ◽  
Pearson Correlation ◽  
Significant Negative Correlation ◽  
Therapeutic Drug ◽  
Tertiary Referral Centre ◽  
Faecal Calprotectin ◽  
Drug Levels ◽  
Induction Dose

Abstract Background Therapeutic drug monitoring (TDM) helps guide use of anti-TNF drugs in IBD patients. In addition, higher anti-TNF levels during induction therapy have been shown to be associated with better clinical and endoscopic outcomes. The role of TDM for more novel biologics such as ustekinumab (an anti- IL-12/23 antibody used to treat Crohn’s disease) remains to be elucidated. Aims We set out to investigate correlations between ustekinumab drug levels measured during induction with clinical and biochemical outcomes in patients with Crohn’s disease. Methods Patients with Crohn’s disease commencing treatment with ustekinumab were recruited from a single tertiary referral centre. Standard weight-based induction dosing was used. TDM was performed at week 2 and week 6 following IV induction dose. A drug-tolerant assay (Prometheus) was used. Kruskal-Wallis test was used to examine association between induction dose and ustekinumab levels. CDAI, CRP, and faecal calprotectin (FCP) were measured at week 12. Pearson correlation co-efficient was used to assess the relationship between ustekinumab levels and i)CDAI ii)CRP and iii)FCP at week 12. Results A total of 38 ustekinumab levels in 21 patients were measured. Week 2 ustekinumab levels were available for 17 patients, 16 (94.1%) of whom had levels of greater or equal to 25μg/mL. (1 patient had a level of 19.5μg/mL.) Week 6 ustekinumab levels were available for 21 patients; median 15μg/mL (IQR 9.9–21.3). No patients had detectable antibodies to ustekinumab. There was no significant association between absolute induction dose and week 6 ustekinumab levels; p=0.46. Of the 21 patients with week 6 levels, CDAI, CRP and FCP were available for 18, 18 and 16 patients respectively; Median CDAI 103(IQR 42–249), median CRP 2.3mg/L(IQR 1.0–11.3), median FCP 269μg/g(IQR109-932). There was a significant negative correlation between week 6 ustekinumab levels and CDAI; r=-.609, p=0.007. A negative correlation between week 6 ustekinumab levels and FCP was also significant; r=-.526, p=0.037. There was no significant correlation between week 6 ustekinumab levels and CRP; r=-.259, p=0.298. Conclusions We have demonstrated inter-patient variation in drug pharmacokinetics at week 6 following induction dose of ustekinumab in patients with Crohn’s disease. Drug levels at week 6 are significantly associated with clinical and biochemical markers of disease activity (CDAI, faecal calprotectin) at week 12. Measurement of week 6 ustekinumab levels may aid early identification of patients at risk of primary non-response to ustekinumab. Funding Agencies Testing provided by Prometheus

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn’s disease – a regional multi-center pilot study

2020 ◽  
Vol 58 (05) ◽  
pp. 439-444 ◽  
Author(s):  
Anne Kerstin Thomann ◽  
Lucas-Alexander Schulte ◽  
Anna-Maria Globig ◽  
Peter Hoffmann ◽  
Thomas Klag ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Pilot Study ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Roc Curve ◽  
Response To Therapy ◽  
Therapeutic Drug ◽  
Serum Concentrations ◽  
Serum Samples ◽  
Area Under Roc Curve

Abstract Background and aim The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn’s disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. Methods Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. Results Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). Conclusion Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.

scholarly journals Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review

F1000Research ◽  
2021 ◽  
Vol 9 ◽  
pp. 316
Author(s):  
Phinga Do ◽  
John Andersen ◽  
Ashish Patel ◽  
Gaith Semrin ◽  
Luis Sifuentes-Dominguez ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Chart Review ◽  
Pediatric Patients ◽  
Retrospective Chart Review ◽  
Previous Treatment ◽  
Therapeutic Drug ◽  
Duration Of Treatment ◽  
Drug Levels

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn’s disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient’s clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

2021 ◽  
Author(s):  
Xavier Roblin ◽  
Capucine Genin ◽  
Stéphane Nancey ◽  
Nicolas Williet ◽  
Pauline Veyrard ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Maintenance Therapy ◽  
Group Treatment ◽  
Treatment Discontinuation ◽  
Dose Optimization ◽  
Secondary Loss ◽  
Loss Of Response ◽  
Trough Levels

Abstract Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels &gt; 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn’s disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P &lt; 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (&gt;24 months) than in the optimization group (13.3 months, P &lt; 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin &gt;500 μg/g (HR, 3.53; 95% CI, 1.16–10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (&gt;2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13–0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. Conclusion In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are &gt;4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Features of very early-onset inflammatory bowel disease: the experience of the Federal Pediatric Center

2021 ◽  
Vol 19 (3) ◽  
pp. 5-13
Author(s):  
P.V. Shumilov ◽  
◽  
A.E. Shchigoleva ◽  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Primary Immunodeficiency ◽  
Bowel Disease ◽  
Early Onset ◽  
Activity Index ◽  
Response To Therapy ◽  
Inflammatory Bowel

Objective. To clarify the incidence of monogenic IBD-like diseases and the features of clinical course and response to therapy of major types of inflammatory bowel diseases (IBD) among children under the age of 6 with manifestation of the disease. Patients and methods. The study included 135 children under the age of 6 with manifestation of IBD; in the comparison group, there were 128 children after the age of 6 with manifestation of IBD (97 children with ulcerative colitis (UC) and 31 children with Crohn’s disease (CD)) who were observed for at least 1 year. All children underwent a standard examination, including calprotectin and antineutrophil antibodies testing, determination of activity by the Pediatric Ulcerative Colitis Activity Index (PUCAI) or the Pediatric Crohn’s Disease Activity Index (PCDAI), depending on the nosology. Children with the onset of IBD under 6 years of age underwent a genetic testing using Primary Immunodeficiency Panel by next-generation sequencing. All children were analyzed for efficacy of therapy during catamnestic observation. Results. It was revealed that in the study group the incidence of monogenic IBD-like diseases was 6.7%, of UC – 71.1%, of CD – 22.2%. Major types of IBD with very early onset differed little in their clinical, endoscopic and laboratory features from the forms with manifestation at an older age. In most cases, both CD (57%) and UC (71%) were characterized by low activity. Very earlyonset CD was characterized by isolated localization of the colon (53%, p = 0.037) and a non-stenotic and non-penetrating behaviour of the disease (60% of cases). The leading clinical symptoms were diarrhea (67%) and blood in the stool (63%, p = 0.04). Very early-onset UC was characterized by total lesion of the colon (84%, p = 0.001) and the development of anemia (48%, p = 0.01). Among children with very early-onset UC, the percentage of glucocorticosteroid-dependence and glucocorticosteroid-resistance was high, but anti-TNFα therapy was prescribed late. Conclusion. It is advisable to observe children with very early-onset IBD in federal multidisciplinary clinics, where there is experience in managing patients with this pathology. Key words: inflammatory bowel disease, very early onset, Crohn’s disease, ulcerative colitis, primary immunodeficiency, treatment, children

Tu1167 Infliximab Is More Immunogenic and Reaches Lower Trough Levels in Ulcerative Colitis Patients Compared to Crohn's Disease Patients

2013 ◽  
Vol 144 (5) ◽  
pp. S-780 ◽  
Author(s):  
Haggai Bar-yoseph ◽  
Yehuda Chowers ◽  
Shomron Ben-Horin ◽  
Matti Waterman
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Trough Levels

scholarly journals THE IMPACT OF INTERMEDIATE TITER ANTIBODIES TO ADALIMUMAB (ATA) AND INFLIXIMAB (ATI) ON CLINICAL OUTCOMES IN PATIENTS WITH CROHN’S DISEASE (CD) OR ULCERATIVE COLITIS (UC)

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S57-S57
Author(s):  
Chaoyang Wang ◽  
Mazen Tolaymat ◽  
Raymond Cross
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Outcomes ◽  
High Titer ◽  
Complete Response ◽  
Response To Therapy ◽  
Loss Of Response ◽  
Titer Group ◽  
The Impact

Abstract Background Anti-TNF drugs, adalimumab (ADA) and infliximab (IFX), are effective treatments for ulcerative colitis (UC) and Crohn’s disease (CD). However, 30% of patients do not respond to treatment (primary non-response) and 40% lose response over time (loss of response). Loss of response is often due to development of antibodies to ADA (ATA) and IFX (ATI). While it is known that undetectable or low ATA/ATI titers (&lt;200 ng/mL) are associated with better outcomes and high ATA/ATI titers (&gt;1000 ng/mL) are associated with poor outcomes, the significance of intermediate ATA/ATI titers (200–999 ng/mL) is not well understood. This study aims to investigate the impact of intermediate ATA/ATI titers on outcomes in CD and UC patients. Methods A retrospective chart review was conducted on CD and UC patients to determine associations between intermediate ATA/ATI titers and adverse clinical outcomes. The primary clinical outcome of interest is persistence on anti-TNF therapy 1 year after measurement of ATA/ATI titers. Secondary clinical outcomes of interest include clinical response to therapy 1 year after measurement of ATA/ATI titers. Participants consist of UC or CD patients treated with IFX or ADA at the University of Maryland IBD Program between October 2016 and October 2019 that had at least one measurement of ADA/ IFX and ATA/ATI during the study period. Results 376 patients were identified (ADA=157 and IFX=219). 271 of 322 low titer patients persisted on their original anti-TNF compared to 9 of 15 intermediate titer patients (p=0.026) and 1 of 10 high titer patients (p&lt;0.0001) (Table 1). The odds ratio (OR) of persistence comparing intermediate titer to low was 0.26 (0.09 to 0.80) and comparing high titer to low was 0.02 (0.00 to 0.14). In the low titer group, 47, 33, and 251 of 331 patients had no, partial, or complete response to therapy, respectively. In the intermediate titer group: 6, 1, and 8 of 15 patients, had no, partial or complete response; in the high titer group: 3, 1, and 3 of 10 patients, had no, partial, or complete response (Table 2). The difference in distribution of patients who showed no, partial, and complete response was significantly different between low titer patients and intermediate titer patients (p=0.019), but not different between intermediate titer and high titer patients (p=0.440). Conclusion Patients with intermediate titers were more likely than patients with low titers to lose response to anti-TNF and require a change anti-TNF therapy. Although our sample size of patients with intermediate titers was small, providers should consider dose optimization of anti-TNF with or without addition of an immune suppressant when intermediate titers are present. An alternative approach would be to repeat drug and antidrug antibody levels to assess for worsening pharmacokinetics. Persistence on original anti-TNF 1 year after first measurement in low, intermediate, and high titer patients (Fisher’s test). Response to therapy 1 year after first measurement in low, intermediate, and high titer patients (Fisher’s test).

scholarly journals Efficacy and tolerability of certolizumab pegol in Crohn's disease in clinical practice

2018 ◽  
Vol 90 (6) ◽  
pp. 74-80 ◽  
Author(s):  
O V Knyazev ◽  
A V Kagramanova ◽  
A A Lishchinskaya ◽  
N G Samsonova ◽  
N V Orlova ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Dose Escalation ◽  
Certolizumab Pegol ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Predictors Of Response ◽  
Tnf Α ◽  
Previously Treated

Aim. To assess the efficacy and tolerance of certolizumab pegol (CP) in patients with Crohn's disease (CD) treated in the Department of inflammatory bowel diseases of the A.S. Loginov Moscow Clinical Research Center and to determine the predictors of response to therapy. Materials and methods. All patients with CD who had received the treatment of CP were observed prospectively for at least 6 months or until the date of discontinuation of the drug. The effectiveness of the study was assessed response to therapy by the 6th week, maintaining the clinical response (6th and 26th weeks), the dynamics of endoscopic parameters by the 10th and 54th week of therapy, long-term maintenance of remission, healing fistula. Used univariant and multivariate analyses of predictors of response to treatment. Results and discussion. The study included 39 patients: 12 (30.7%) men and 27 (69.3%) female, the average duration of observation was 104 weeks. The interdepartmental range was in the range from 28 to 158 weeks. Clinical improvement occurred in 38 out of 39 (97.4 %) patients with CD. Comparative analysis of response to treatment with CP have bionaive patients previously treated with another inhibitor of TNF-α. In the group of bionaive response to therapy in a month, 6 months and at the end of the observation period occurred at 100.0%, 95.0% and 95.0%, respectively. In the group of patients previously treated with GSI, the response rate was about 94.4 %, 88.9 % and 77.7% week 54 endoscopic response and endoscopic remission was maintained in 46,2% and 30,1% patients, complete healing of the mucosa on the background of maintenance therapy, CP, was preserved in 20.5% of patients with Crohn's disease. In the group of patients with perianal lesions (n=13) complete closure of all fistulas was observed in 5 (38.6 %) patients, partial response was observed in 4 patients (30,7%) patients, in 4 (30.7 %) closure of fistulas occurred. The frequency of adverse events was 0 cases (0.0%). The dose escalation was required in 3 patients (7,7%) patients with CD. Dose escalation in our study required patients with high initial CDAI and previous inefficiencies of the other two inhibitors of TNF-α. Reliable predictors of secondary loss of response and need for dose escalation of the drug has been the continued level of CRP >5 mg/l after 2 weeks initiation of therapy CP and smoking. Conclusion. The obtained results demonstrate the efficacy and tolerability profile of CP appropriate for long-term CD therapy in real clinical practice.

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