Adalimumab Dose-Escalation Therapy Is Effective in Refractory Crohn’s Disease Patients with Loss of Response to Adalimumab, Especially in Cases without Previous Infliximab Treatment

Suzuki, Taketo; Mizoshita, Tsutomu; Sugiyama, Tomoya; Hirata, Yoshikazu; Kimura, Yoshihide; Suzuki, Yuka; Yamada, Terumasa; Tsukamoto, Hironobu; Mizushima, Takashi; Sugimura, Naomi; Katano, Takahito; Tanida, Satoshi; Kataoka, Hiromi; Sasaki, Makoto

doi:10.1159/000496453

Cited by 9 publications

(30 citation statements)

References 29 publications

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“…Sustained clinical response and remission beyond 12 months from the time of dose escalation were reported in 14 studies and ranged from 33% to 90% for response and 28%‐81% for remission 27,31,33‐36,41,42,45‐48,50,51 . Similar rates of loss of response to dose‐escalated treatment (tertiary loss of response) were reported across five studies 27,30,44,45,52 .…”

Section: Resultsmentioning

confidence: 68%

“…32 Sustained clinical response and remission beyond 12 months from the time of dose escalation were reported in 14 studies and ranged from 33% to 90% for response and 28%-81% for remission. 27,31,[33][34][35][36]41,42,[45][46][47][48]50,51 Similar rates of loss of response to dose-escalated treatment (tertiary loss of response) were reported across five studies. 27,30,44,45,52 In the study by Ma et al, 30 over half (56.8%) of those that responded clinically to escalated adalimumab subsequently lost response (median time to tertiary loss of response 47.9 weeks [IQR 24.7-80.3]).…”

Section: Standard Maintenance Dosing Of Infliximab and Adalimumabmentioning

confidence: 84%

“…The majority of clinical efficacy data were from retrospective studies with subcohorts that underwent empiric dose escalation (without the use of TDM) for loss of response to standard treatment. Twenty studies reported clinical outcomes following empiric escalation of maintenance adalimumab 10,23‐41 . Response rates ranged from 33% to 100% (Figure 2), and remission was achieved in 15% to 83% of patients at any point after treatment escalation 10,23‐41 .…”

Section: Resultsmentioning

confidence: 99%

“…10,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Response rates ranged from 33% to 100% (Figure 2), and remission was achieved in 15% to 83% of patients at any point after treatment escalation. 10,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] In 15 of these studies, more than half of the patients regained clinical response after dose escalation. [23][24][25][27][28][29][30][31][32]…”

Section: Standard Maintenance Dosing Of Infliximab and Adalimumabmentioning

confidence: 99%

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Systematic review: efficacy of escalated maintenance anti‐tumour necrosis factor therapy in Crohn's disease

Mattoo

Basnayake

Connell

et al. 2021

Aliment Pharmacol Ther

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Summary Background Loss of response to anti‐TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). Aims To perform a systematic review assessing the efficacy of escalated maintenance anti‐TNF therapy in CD. Methods EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full‐text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. Results A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%‐100%) and remission (15%‐83%) after empiric dose escalation for loss of response to standard anti‐TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose‐escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure‐response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end‐points. Strategies including Bayesian dashboard‐dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long‐term outcomes. Conclusions Empiric escalation of maintenance anti‐TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

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Section: Resultsmentioning

confidence: 68%

Section: Standard Maintenance Dosing Of Infliximab and Adalimumabmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Standard Maintenance Dosing Of Infliximab and Adalimumabmentioning

confidence: 99%

See 2 more Smart Citations

Systematic review: efficacy of escalated maintenance anti‐tumour necrosis factor therapy in Crohn's disease

Mattoo

Basnayake

Connell

et al. 2021

Aliment Pharmacol Ther

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“…This shows no relevant differences with the previous data and constitutes one main finding of our study: dose escalation was needed more often in patients with prior anti-TNF use. In fact, the vast majority of the included studies evaluating both naïve and non-naïve patients showed a greater incidence in the loss of response in those non-naïve [ 30 , 34 , 35 , 60 , 81 , 84 , 111 , 121 , 132 , 161 , 163 , 168 , 192 , 193 ].…”

Section: Discussionmentioning

confidence: 99%

Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis

Guberna

Nyssen

Chaparro

et al. 2021

JCM

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Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. Selection: prospective and retrospective studies assessing DI in Crohn’s disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn’s disease or those where DI was based on therapeutic drug monitoring. Data synthesis: effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn’s disease), anti-TNF drug and follow-up. Results: One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24–32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31–47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28–43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48–78%; I2 = 99%; 32 studies) and 48% (95% CI: 39–58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents―and, consequently, DI―occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.

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Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study

Verstegen

Shrader

Balevic

et al. 2022

Arthritis Care & Research

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Objective To determine the dose–response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). Methods Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long‐term follow‐up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. Results Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66–1.04] and 0.83 mg/kg body weight [IQR 0.75–0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. Conclusion This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

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Adalimumab Dose-Escalation Therapy Is Effective in Refractory Crohn’s Disease Patients with Loss of Response to Adalimumab, Especially in Cases without Previous Infliximab Treatment

Cited by 9 publications

References 29 publications

Systematic review: efficacy of escalated maintenance anti‐tumour necrosis factor therapy in Crohn's disease

Systematic review: efficacy of escalated maintenance anti‐tumour necrosis factor therapy in Crohn's disease

Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis

Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study

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