Post-Induction Adalimumab Concentration is Associated with Short-Term Mucosal Healing in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Mucosal healing is associated with favourable therapeutic outcomes in patients with ulcerative colitis [UC]. We investigated whether adalimumab concentrations during induction therapy are associated with short-term mucosal healing [STMH] in UC patients. METHODS: This was a retrospective, single-centre study including consecutive UC patients treated with adalimumab from June 2005 to May 2014, who underwent an endoscopy both at baseline and after induction therapy [weeks 8-14] and at least one serum sample available at week 2 and/or week 4. STMH was defined as Mayo endoscopic sub-score of ≤1 with a baseline sub-score of ≥2. Adalimumab concentrations were evaluated using an in-house developed enzyme-linked immunosorbent assay. RESULTS: The study population consisted of 43 patients, the majority of whom [n = 38] were prior infliximab failures; the rest showed primary non-response [PNR, n = 5]. Twelve patients [27.9%] achieved STMH. Patients with STMH had higher adalimumab concentrations at week 4 compared to those without [10.6 vs 7.4 µg/ml, p = 0.014]. A receiver operating characteristic [ROC] analysis identified an adalimumab concentration threshold at week 4 of 9.4 µg/ml (area under the ROC curve [AUROC]: 0.778) and 7.5 µg/ml [AUROC: 0.798], after excluding patients with PNR to infliximab, to be associated with STMH. Multiple logistic regression analysis, after excluding patients with PNR to infliximab, identified adalimumab concentration ≥7.5 µg/ml at week 4 (odds ratio [OR]: 15.7; 95% confidence interval [CI]: 1.3-185; p = 0.029) and baseline endoscopic Mayo score 3 [OR: 0.13; 95% CI: 0.02-0.98; p = 0.047] as factors independently associated with STMH. CONCLUSIONS: This study, reflecting real-life clinical practice, demonstrated that post-induction adalimumab concentrations are associated with STMH, while higher baseline mucosal inflammation is related to lack of STMH in UC.

Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study.

BACKGROUND: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized. OBJECTIVE: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions. DESIGN: Retrospective cohort. SETTING: Single IBD tertiary referral center. PATIENTS: 917 consecutive patients with IBD who initiated anti-TNF therapy. MEASUREMENTS: Skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers. RESULTS: During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions. LIMITATION: Retrospective nature and no matched control group of patients not receiving anti-TNF therapy. CONCLUSION: Skin lesions occur frequently in association with anti-TNF therapy but rarely require discontinuation of therapy. Close surveillance and early referral to a dedicated dermatologist are recommended. PRIMARY FUNDING SOURCE: Research Foundation Flanders (FWO), Belgium; Geconcerteerde Onderzoekacties of KU Leuven; and Janssen Biologics.

IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab.

OBJECTIVE: The chimeric anti-tumor necrosis factor-alpha antibody infliximab is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma1 chain may also be implicated as it expresses G1m1 and G1m17 allotypes. This allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype commonly expressed in Caucasoid populations. METHODS: As G1m allotypic divergence may explain the presence of ATI or may influence their concentration, a genotyping method was developed and validated to determine antithetical (i.e. mutually exclusive) G1m3 and G1m17 allotypes (amino acid 120 of CH1 according to the international ImMunoGeneTics information system unique numbering) at the IGHG1 gene level (CH1 359g/a nucleotide polymorphism). Two hundred forty-five blood donors and 118 previously described patients suffering from Crohn's disease, treated with infliximab, and having developed ATI in 73 of them, were genotyped. RESULTS: The IGHG1 CH1 359g/a polymorphism does not depart from the Hardy-Weinberg equilibrium in the control population, and allele frequencies were similar in controls and patients. No association was found between the patient G1m allotypes and the presence of ATI or their concentration. It remains possible that anti-Gm1 antibodies are not well detected by the enzyme-linked immunosorbent assays used for ATI detection and/or that the G1m allotypes are minor antigens on IgG1. CONCLUSION: The IGHG1 polymorphism does not seem to play a major role in the induction of ATI. Further analyses will be required to determine whether it is also the case for humanized or fully human antibodies bearing the same G1m allotypes.

Role of biomarkers in the diagnosis of inflammatory bowel disease.

In the diagnostic work up of a patient suspected of having inflammatory bowel disease (IBD), biomarkers are helpful in prioritizing further examinations, including endoscopy, and/or in the decision to start or intensify treatment. C-reactive protein has many advantages, but its short half-life makes this a particularly good marker in the detection and follow up of disease activity in Crohn's disease. In contrast, ulcerative colitis (with the exception of severe colitis) has only a modest-to-absent C-reactive protein response despite active inflammation. As stools are easy accessible in IBD patients, fecal markers hold a specific promise and recent studies even claim superiority of fecal markers over serum markers. A number of neutrophil-derived proteins shedding in stools have been studied. Calprotectin and lactoferrin are probably the most promising given their abundance in granulocytes and their stability and resistance to degradation. Although calprotectin and lactoferrin are very sensitive markers to detect inflammation in the gastrointestinal tract, they are not specific for IBD and increased levels are also found in neoplasia, NSAID abuse, infections and polyps. In children with abdominal symptoms and diarrhea, a positive test for calprotectin or lactoferrin may prioritize endoscopy. The antimicrobial and antiglycan antibodies detected in many IBD patients have no place in the diagnostic work up, except in cases of colitis-type unclassified, in which anti-Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic antibodies still have the best accuracy. Nevertheless, these markers are often negative in this setting. The interest in antimicrobial and antiglycan antibodies has recently been increased as they have shown to act as surrogate markers of complicated aggressive disease.