Higher Adalimumab Trough Levels Are Associated with Histologic Remission and Mucosal Healing in Inflammatory Bowel Disease
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Abstract:
(1) Many patients with inflammatory bowel disease (IBD) in endoscopic remission have persistent histologic activity, which is associated with worse outcomes. There are limited data on the association between adalimumab drug concentrations and histologic outcomes using validated histologic indices. We aimed to assess the relationship between adalimumab concentrations and the Robarts Histopathology Index (RHI). (2) Patients from a tertiary IBD center from 2013 to 2020 with serum adalimumab (ADA) trough concentrations measured during maintenance therapy (≥14 weeks) and a colonoscopy or flexible sigmoidoscopy with biopsies performed within 90 days of drug level were included. Blinded histologic scoring using the RHI was performed. Primary analysis assessed the relationship between adalimumab drug concentrations and histologic remission using receiver operating characteristic curve analysis. (3) In 36 patients (26 Crohn’s Disease, 9 ulcerative colitis, 1 indeterminate), median adalimumab concentrations were higher (17.3 ug/mL, 12.2–24.0) in patients with histologic remission compared to those without (10.3 ug/mL, 6.8–13.9, p = 0.008). The optimal ADA concentration identified using the Youden threshold was ≥16.3 ug/mL (sensitivity 70%, specificity 90%). Patients with ADA ≥ 16.3 ug/mL had higher histologic remission rates (78%) compared to lower ADA concentrations (14%, p= 0.002), as well as higher mucosal healing rates (86%) compared to lower levels (12%, p = 0.001). Symptoms correlated weakly and non-significantly with both histologic (RHI) scores (r = 0.25, p = 0.2) and adalimumab concentrations (r = 0.05, p = 0.8). (4) The current study demonstrated that higher serum adalimumab concentrations (≥16.3 ug/mL) are needed for histologic remission and mucosal healing assessed using the RHI.Keywords:
Histopathology
Sigmoidoscopy
목ì ì ì ì¤í ë¡ì´ëë ë©´ììµì ì ì¹ë£ ì¤ìë ë°ë³µíì¬ ì¬ë°íë ëì¹ì± í¬ëë§ì¼ìì Adalimumab (Humira®, AbbVie, Chicago, IL, USA)ì ì¬ì©íì¬ ì¹ë£ 결과를 íê°íê³ í¨ì©ì±ì ììë³´ê³ ì íìë¤. ëìê³¼ ë°©ë² ë¹ê°ì¼ì± ëì¹ì± í¬ëë§ì¼ì¼ë¡ Adalimumab 주ì¬ì¹ë£ë¥¼ ìíí íìë¤ì ëìì¼ë¡ íí¥ì ì¼ë¡ ììììì ë¹êµ ë¶ìíìë¤. 기ì ì§í, í¬ëë§ì¼ ìì, ë³ì©ì¹ë£ ì½ë¬¼ì ì 무, 기존 ì¹ë£ë¡ ë°ìí ë¶ìì©ì ì¡°ì¬íìê³ ì¹ë£ ì íì ì ë°©ê³¼ ì ë¦¬ì²´ê° ë´ ì¸í¬ ë° í¼í, ì¤ì¬í©ë°ëê» ë° ìµëêµì ìë ¥ì ë¹êµíìë¤. ì¼ì¦ê³¼ í©ë°ë¶ì¢ ì ì¬ë° ì 무, ë³ì©ì¹ë£ ì½ë¬¼ì ì¡°ì ì¬ë¶, ì´ìë°ì ë°ì ì¬ë¡ë¥¼ íì¸íì¬ Adalimumab í¬ì¬ì ìì ì±ê³¼ í¨ì©ì±ì íê°íìë¤. ê²°ê³¼ Adalimumab í¬ì¬ ì ì ë³ê¸°ê°ì íê· 55.4ê°ì(13-121ê°ì)ì´ìì¼ë©° ì£¼ì¬ í ì¶ì ê´ì°° 기ê°ì íê· 9.2ê°ì(6-18ê°ì)ì´ìë¤. 18ëª 30ì 모ëìì ì ì ì¤í ë¡ì´ë ì¬ì©ì ì¤ë¨í ì ììì¼ë©° ì¼ì¦ ìíê° íì¸ëìë¤. ì ë°©ê³¼ ì 리체ê°ë´ ì¼ì¦, ìµëêµì ìë ¥ì ì ìí í¸ì ì ë³´ìì¼ë©° ì¤ì¬í©ë°ëê»ë ì°¨ì´ë¥¼ ë³´ì´ì§ ììë¤. 5ììì í¬ëë§ì¼ì ì¬ë°ì´ ë°ìíìì¼ë 4ìì í ë ¼ëí ì¤í ë¡ì´ë주ì ì ë¡ ì¼ì¦ ì¡°ì ì´ ê°ë¥íìì¼ë©°, 1ìì methotrexate ë³ì© í¬ì¬ í ì¡°ì ì´ ê°ë¥íë¤. Adalimumab í¬ì½ ì¤ ë°ìí ì´ì ë°ìì ëëë¬ê¸°(2ëª )ì 주ì¬ë¶ì ë°ì(1ëª )ì´ ë°ìíìì¼ë©° 주ì¬ë¶ì ë°ì 1ëª ì í¬ì½ì ì¤ë¨í´ì¼ íë¤. ê²°ë¡ Adalimumabì ëì¹ì± í¬ëë§ì¼ íìë¤ìì ì¼ì¦ì ìíìí¤ê³ ì ì ì¤í ë¡ì´ë í¬ì½ì ì¤ì¼ ì ìë í¨ê³¼ì ì¸ ì¹ë£ë²ì´ë¤. Keywords: Adalimumab (Humira®, AbbVie), Refractory uveitis, Tumor necrosis factor-α
Refractory (planetary science)
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Sigmoidoscopy
Colorectal cancer screening
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Background
Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). There is a relationship between adalimumab concentration and clinical response but it has never been quantified individually.Objectives
To describe the individual relationship between adalimumab concentration and disease activity in RA patients and to select an adalimumab target concentration necessary to reach either a low disease activity or clinical remission.Methods
We measured adalimumab concentration in 127 samples from 30 RA patients who received 40 mg subcutaneously every other week. Disease activity score (DAS 28) were available at baseline, and at weeks 6, 12, 24 and 52. The relationship between adalimumab concentrations and DAS 28 was described by pharmacokinetic-pharmacodynamic (PK-PD) modelling using a direct inhibitory model.Results
Median adalimumab concentrations increased over all the year whereas median DAS 28 decreased. At steady state, median adalimumab concentration [min-max] was 7.8 mg/L [1.8-15.0] and median DAS 28 was 2.9 [0.8-6.3]. The concentration-response relationship of adalimumab was well described by the direct inhibitory model. For a typical patient, adalimumab concentration required to decrease baseline DAS28 by 2 was 11.8 mg/L. The relationship between baseline DAS 28 and adalimumab concentration at steady state is displayed in figure 1. It shows that, if baseline DAS 28 is 6, the steady state adalimumab concentration necessary to achieve a low disease activity is 10 mg/L with 25%>75% confidence interval of 5-20 mg/L. To achieve remission, the required adalimumab concentration is 15 mg/L [8-30 mg/L].Image/graph
Conclusions
This is the first study describing the individual concentration-effect relationship of adalimumab in RA. This model can be used to select the target concentration of adalimumab when therapeutic drug monitoring is applied.Acknowledgements
Pr. Christian Marcelli. CHU Caen, Pr. René-Marc Flipo. CHU Lille, Pr. Patrice Fardellone. CHU AmiensDisclosure of Interest
None DeclaredPharmacodynamics
Therapeutic Drug Monitoring
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Adalimumab is an effective treatment for Crohn's disease (CD). We aimed to describe the early patterns of use, efficacy and response to adalimumab in four regions of New Zealand.Prospectively collected CDAI data were used to examine adalimumab continuation rates in CD patients. Reasons for adalimumab cessation were determined and phenotypic characteristics of those remaining on adalimumab were examined.194 patients (100 female) from four centres were included. Indications for adalimumab included CDAI>300 (59.8%), extensive small intestinal disease (21.1%), stoma with active disease (4.6%), risk of short gut syndrome (7.7%) and other (6.7%). The mean follow-up was 20 months (252.8 patient years of data). Adalimumab continuation rates at 6, 12, 24 and 30 months were 92.7%, 87.3%, 76.6% and 67.4%, respectively. Patients with penetrating disease behaviour were more likely to continue on adalimumab (p<0.005). There was a significant reduction in mean CDAI from 357 to 110 (p<0.0001) over a 6-month period. The mean (range) number of days spent in hospital per patient in the year prior and after adalimumab initiation were 3.5 (0-38) days and 1.9 (0-67) days, respectively (p<0.0001).Adalimumab continuation rate in this multicentre CD population was higher than other populations. This may be due to adalimumab being used more commonly as the initial biologic drug in New Zealand.
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TNF concentrations stabilize in patients with rheumatoid arthritis during long-term adalimumab therapy and are associated with antidrug antibodies.
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Background
Many patients with rheumatoid arthritis (RA) are successfully treated with tumour necrosis factor inhibitors (TNFi). We recently developed a novel assay that can quantify TNF in the presence of large amounts of TNFi, i.e. a 'drug-tolerant' assay. We showed in RA patients that TNF levels increased and stabilised during adalimumab treatment due to complex forming between TNF and adalimumab. In the presence of adalimumab, all TNF was in complex and biologically inactive. Once in remission, some patients can discontinue the TNFi for a prolonged period. It is unclear how long adalimumab levels are detectable and TNF complexes are formed after the last adalimumab administration.Objectives
To investigate adalimumab levels and complexed TNF levels 6 months after the last adalimumab administration.Methods
TNF and adalimumab levels were measured using a novel drug-tolerant competition enzyme-linked immunosorbent assay (ELISA), and a regular ELISA, respectively, in 11 consecutive RA patients with stable low disease activity (disease activity score of 28 joints<3.2) who discontinued adalimumab for 6 months (prior dose: 40 mg every 2 weeks). Blood samples were drawn prior to adalimumab discontinuation and 3 and 6 months thereafter.Results
After the last adalimumab administration, mean adalimumab level decreased from 5.5 (SD 2.9) to 0.55 (0.52) and 0.11 (0.13) μg/mL at 3 and 6 months after treatment discontinuation, respectively (figure 1A). In contrast, complexed TNF levels remained stable for prolonged periods of time: in 8 patients TNF levels at 3 months were indistinguishable from levels seen at baseline, on standard-dose adalimumab (figure 1B). After 6 months, TNF still remained stable in patients with adalimumab concentrations above 0.1 µg/mL (n=4). Overall, mean TNF levels decreased from median 381 (inner quartiles 16; 707) to 2902; 755 and 832; 532 pg/mL at 3 and 6 months after treatment discontinuation, respectively. In 5 patients, TNF levels decreased significantly. In those patients, adalimumab levels dropped to, or below the detection limit.Conclusions
This is the first study showing that TNF is still in complex with adalimumab in the majority of patients 6 months after the last administration. Therefore, one may wonder at which point in time a patient has truly discontinued adalimumab treatment.Disclosure of Interest
M. l'Ami: None declared, L. Berkhout: None declared, M. Nurmohamed Grant/research support from: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, Speakers bureau: Pfizer, AbbVie, Roche, BMS, MSD, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Sanofi, and Celgene, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, UCB, Consultant for: AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, UCB, M. Boers: None declared, J. Ruwaard: None declared, F. Hooijberg: None declared, T. Rispens Grant/research support from: Genmab, Speakers bureau: Pfizer, AbbVie and Regeneron, G. Wolbink Speakers bureau: Pfizer, UCB, AbbVie, Biogen, BMSDiscontinuation
TNF inhibitor
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강직성 척추염은 몸통 뼈대와 큰 말초 관절 그리고 근육힘줄뼈 부착부위에 발생하는 만성 염증성 류마티스 질환이다. Adalimumab은 anti-tumor necrosis factor(TNF) 중 하나로 강 직성 척추염의 치료에 투여한다. Adalimumab 이 강직성 척추염의 징후와 증상의 치료에 효과적이기는 하지만, 강직성 척추염 환자에 서 뼈의 발생 혹은 재형성과 TNF 사이의 뚜렷한 연관성은 아직 밝혀지지 않았다. 그 리고adalimumab 치료 후에 이전에 손상되었던 천장관절의 회복이 영상의학적으로 증명 된 적은 극히 드물다. 여기서 우리가 소개하는 29세 남자는 이전에 천장관절의 염증성 변화를 보이는 강직성 척추염을 진단 받았던 자로, adalimumab 치료 전후에 영상의학적 변화를 비교해 보았다. 컴퓨터 단층촬영 영 상에서 adalimumab 치료 후 양측 천장관절 의 관절강이 좁아진 소견없이 미란성 변화들 이 거의 회복된 것을 볼 수 있었다. 이것은 adalimumab 치료 후에 강직성 척추염의 징 후 와 증상의 호전뿐만 아니라 이와 함께 천 장관절의 골미란이 관절강이 좁아지는 소견 없이 회복된 첫 번째 증례라고 할 수 있다.
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Objectives: In patients with chronic human immunodeficiency virus (HIV)-related diarrhea undergoing lower endoscopy, the decision to perform flexible sigmoidoscopy or colonoscopy is controversial. The purpose of this study is twofold: 1) to evaluate the diagnostic yield of colonoscopy in a large group of patients with chronic HIV-related diarrhea and negative stool studies, and 2) to determine whether colonoscopy is superior to flexible sigmoidoscopy in this setting. Methods: All HIV-infected patients with chronic diarrhea who were referred for diagnostic colonoscopy at Bellevue Hospital Center between January 1992 and December 1996 were identified. Patient charts, pathology reports, and endoscopy records were reviewed. Results: During the 5-yr study period, 317 consecutive patients with chronic unexplained diarrhea undergoing colonoscopy were identified. A potential cause of diarrhea was found in 116 patients (36.6%). Cytomegalovirus was the most common pathogen detected (24%). The yield of colonoscopy was significantly higher in patients with a CD4 count of < 100 cells/mm3 than in those with higher CD4 counts (44.8%vs 6.4%, p < 0.0001). Thirty percent of pathogens and 75% of lymphomas were identified only on biopsies taken from the proximal colon, well beyond the reach of the flexible sigmoidoscope. Importantly, 94% of the pathogens that were found only in the proximal colon were organisms for which effective therapy is currently available. Conclusions: Colonoscopy is superior to flexible sigmoidoscopy in HIV-infected patients with chronic unexplained diarrhea. If flexible sigmoidoscopy had been performed instead of colonoscopy, 30% of pathogens would have been missed and 75% of lymphomas would have escaped detection.
Sigmoidoscopy
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This Summary of Research overviews the results of the VOLTAIRE-X study (NCT03210259), which looked at what happened when people with plaque psoriasis continually took the adalimumab reference product (adalimumab RP; known by the brand name Humira
Biosimilar
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