Immunogenicity and Loss of Effectiveness of Biologic Therapy for Inflammatory Bowel Disease Patients Due to Anti-Drug Antibody Development.

Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD.

A personalized network framework reveals predictive axis of anti-TNF response across diseases.

Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we use a computational approach termed Disruption Networks to generate a data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. This data type extends beyond the "feature level space", to the "relations space", by quantifying individual-level breaking or rewiring of cross-feature relations. Applying Disruption Networks to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response.

Ustekinumab treatment in ulcerative colitis: Real-world data from the Swedish inflammatory bowel disease quality register.

BACKGROUND: Real-world data on clinical outcomes of ustekinumab in ulcerative colitis are lacking. OBJECTIVE: To assess short- and long-term clinical outcomes of ustekinumab in ulcerative colitis. METHODS: Adult ulcerative colitis patients without previous colectomy starting ustekinumab treatment up until 11 December 2020 were identified through the Swedish Inflammatory Bowel Disease Register (SWIBREG). Prospectively recorded data were extracted from the SWIBREG. The primary outcome was persistence to ustekinumab 16 weeks after treatment initiation. Secondary outcomes included drug persistence beyond week 16, clinical remission (defined as a patient-reported Mayo rectal bleeding subscore = 0 and stool frequency subscore ≤1), biochemical remission (defined as faecal-calprotectin <250 µg/g) and changes in health-related quality of life (HRQoL), as measured by the Short Health Scale (SHS). Logistic regression was used to identify potential predictors of ustekinumab persistence at 16 weeks. RESULTS: Of the 133 patients with ulcerative colitis, only three were naïve to biologics and tofacitinib. The persistence rates of ustekinumab were 115/133 (86%) at 16 weeks and 89/133 (67%) at last follow-up, that is, after a median follow-up of 32 (interquartile range 19-56) weeks. The clinical remission rates were 17% at 16 weeks and 32% at the last follow-up. The corresponding rates for biochemical remission were 14% and 23%. The median faecal-calprotectin concentration decreased from 740 µg/g at baseline to 98 µg/g at the last follow-up (p < 0.01, n = 37). Improvement was seen in each dimension of the SHS between baseline and last follow-up (p < 0.01 for each dimension, n = 46). Male sex was associated with ustekinumab persistence at 16 weeks (adjusted odds ratio = 4.00, 95% confidence interval: 1.35-11.83). CONCLUSION: In this nationwide real-world cohort of ulcerative colitis patients with prior drug failures, including other biologics and tofacitinib, ustekinumab was associated with high drug persistence rates and improvements in clinical, biochemical and HRQoL measures.

Intestinal healing after anti-TNF induction therapy predicts long-term response to one-year treatment in patients with ileocolonic Crohn's disease naive to anti-TNF agents.

INTRODUCTION: Objective assessment of Crohn's disease (CD) activity in patients treated with anti-tumour necrosis factor (anti-TNF) antibodies is crucial for the prediction of its long-term results. Mucosal healing estimated endoscopically has a strong predictive value; however, only combined assessment together with transmural healing in magnetic resonance enterography (MRE) gives full information about the whole spectrum of inflammatory lesions in CD. AIM: To assess the usefulness of intestinal healing phenomenon in CD, defined as improvement both in endoscopy and MRE, after anti-TNF induction therapy, in predicting long-term results of 1-year treatment. MATERIAL AND METHODS: Twenty-six patients with ileocolonic CD were enrolled into the study. In this group a parallel assessment of disease activity was estimated before and after induction doses of anti-TNF antibodies with ileocolonoscopy and MRE by using appropriate scores. Subsequently the patients were treated until 12 months and then followed-up. The associations between intestinal healing (assessed in MRE and endoscopy), and mucosal and transmural healing with long-term results of 1-year anti-TNF therapy were analysed statistically. RESULTS: The median time of follow-up was 29 months (interquartile range - IQR: 14-46). Intestinal healing was significantly associated with favourable therapeutic outcomes (p = 0.02) and had 75% (IQR: 35-97%) sensitivity and 72% (IQR: 46-90%) specificity in predicting long-term remission. Other parameters were not useful (transmural healing) or their usefulness was of borderline significance (mucosal healing). CONCLUSIONS: Dynamic assessment of intestinal healing is an accurate method in predicting long-term outcomes in CD patients responding to 1-year anti-TNF therapy.

Advances in Therapeutic Drug Monitoring of Biologic Therapies in Inflammatory Bowel Disease: 2015 in Review.

OPINION STATEMENT: Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNFs) has revolutionized the care of patients with Crohn's disease and ulcerative colitis. These large proteins are potentially immunogenic. Early clinical trials demonstrated an association with both serum concentrations of these agents as well as the presence of antidrug antibodies generated by the host with loss of response. More recent research has provided further evidence to confirm the impact of low drug trough concentrations and antidrug antibodies on subsequent clinical course in CD and UC. Given these clinical implications, treatment algorithms have been developed to aid clinicians in interpreting trough drug levels and antibody concentrations in those with confirmed active disease. Several studies have demonstrated the utility of these approaches. Furthermore, there are growing data supporting the use of therapeutic drug monitoring in a prospective fashion in those patients who are clinically stable on anti-TNF therapies to ensure they are receiving appropriate dosing and have not yet developed antibodies. In addition, for those who have developed low-level antibodies, increasing the dose of an anti-TNF or adding an immunomodulator may help to overcome this immunologic response. Further research is required to assess these proposed strategies, as well as to determine the role of trough drug level assessment and antibody testing for new anti-TNFs and biologic medication with alternative mechanisms of action.

Diagnostic importance of faecal markers in long-term monitoring of anti-TNF-α therapy in primary responders with Crohn's disease.

INTRODUCTION: Monitoring the response to biological treatment in Crohn's disease (CD) is a very important element of the therapeutic optimisation. AIM: To evaluate the usefulness of measuring calprotectin, lactoferrin, and myeloperoxidase in stool as markers of long-term clinical and endoscopic response to anti-tumour necrosis factor α (anti-TNF) treatment in CD. MATERIAL AND METHODS: The studied group consisted of 35 CD patients treated with anti-TNF-α antibodies. Clinical activity was evaluated using Crohn's Disease Activity Index (CDAI), and the exacerbation of endoscopic changes was evaluated using a Simple Endoscopic Score for Crohn's Disease (SES-CD). The concentration of calprotectin, lactoferrin, and myeloperoxidase was measured using the ELISA method. All measurements were performed three times - before, after 3 months, and after a year of therapy. RESULTS: During anti-TNF treatment the concentrations of all measured faecal markers decreased significantly in relation to baseline values. We observed a significant correlation at all time-points: before the therapy, after 3 months, and 12 months after starting the therapy, between the concentration of calprotectin and SES-CD, calprotectin and CDAI, as well as between lactoferrin and SES-CD, and lactoferrin and CDAI. Myeloperoxidase correlated with both SES-CD and CDAI only after 1 year of treatment. CONCLUSIONS: Faecal calprotectin and lactoferrin are valuable markers of clinical and endoscopic activity of CD in patients treated with anti-TNF antibodies. They are useful in monitoring the response to treatment. The usefulness of myeloperoxidase in this respect remains controversial.

Where are we heading to in pharmacological IBD therapy?

After a relatively long time of failed developments and negative clinical trials in pharmacological inflammatory bowel disease (IBD) therapy we now phase a time of a great number of successful studies and new therapy principles that will most likely make it into clinical practice. This will change the landscape of IBD therapy in future markedly. Many new therapeutic principles have been developed and old ones that seemed to have failed such as anti-sense technology suddenly now provide promising results. Some initially promising therapies will need further development or have failed such as Trichuris suis ova therapy (but not helminth therapy in general), CCR9 targeted therapies or recombinant IL-10. In contrast anti-leukocate trafficking therapies appear to be quite promising. Vedolizumab is the first in class anti-integrin antibody that was approved for the therapy of CD and UC recently. Other anti-integrin antibodies and small molecule adhesion inhibitors will most likely be approved in the next years for IBD therapy. Tofacitinib, a small molecule JAK inhibitor, is a promising candidate for the treatment of UC. Phosphatidylcholine may be a future option for patients with 5-ASA refractory UC or 5-ASA intolerance. The preliminary data for Mongersen, a Smad7 antisense oligonucleotide, are promising despite some concerns about long term effect of TGFß induction. Anti IL6 strategies will hopefully be further evaluated keeping in mind the caveat of a lack of CRP induction in anti-IL6 treated patients. Stem cell transplantation will become an option for patients that have experienced failure of established medications. Fecal microbiota transplantation and also perhaps combined probiotic therapy is a field that will be evaluated in more detail in the near future especially for UC patients. Based on these new developments treatment algorithms need to be updated. This review will reflect these current developments and give a perspective for future IBD therapy.

Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab.

BACKGROUND & AIMS: There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab. METHODS: We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies). RESULTS: Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test). CONCLUSIONS: The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn's disease: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Combination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn's disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial. The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature. METHODS: We performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1 year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed. RESULTS: Eighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n=1984) showed that ADA monotherapy was inferior to combination therapy [OR=0.78 (0.64-0.96), p=0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR=1.08 (0.79-1.48), p=0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR=1.13 (0.69-1.85), p=0.62]. CONCLUSIONS: Combination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1 year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials.

Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies.

PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour necrosis factor (TNF) antibodies. METHODS: De novo malignancies in 666 thiopurine-treated and/or anti-TNF-treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti-TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti-TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. RESULTS: In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82-9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group ≥50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients ≥50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration ≥4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005). CONCLUSIONS: Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF antibodies with or without thiopurines.

Optimizing anti-TNF treatments in inflammatory bowel disease.

BACKGROUND: Failure of anti-TNF treatment in inflammatory bowel disease (IBD) patients can take on several forms, each posing distinct etio-pathogenic considerations and management dilemmas. AIM: The aim of this study is to review the mechanisms responsible for the various forms of anti-TNF failures in IBD and to elucidate strategies for optimizing clinical efficacy. RESULTS: Primary failures of anti-TNF induction therapy occur in up to 40% of patients in clinical trials and in 10-20% in clinical series. Longer disease duration, smoking and several genetic mutations are predisposing factors for primary failures. Curiously, primary non-response is probably not a class-effect phenomenon since switching to another anti-TNF is effective in over 50% of such patients. Secondary loss of response is also a common clinical problem with incidence ranging between 23 and 46% at 12months after anti-TNF initiation. Underlying mechanisms are often related to increased anti-TNF clearance by anti-drug antibodies, but may also include other causes for recalcitrant IBD activity as well as disorders that are unrelated to IBD itself. Astute management begins with verifying the presence of uncontrolled inflammatory IBD activity as a cause for patient's symptoms. Next, it is prudent to consider a trial of wait-and-see approach, since in some patients with mild-moderate symptoms, loss of response may resolve without alteration of therapy. If it does not, measuring anti-TNF trough levels and anti-drug antibodies may clarify the underlying mechanism in individual patients although there are still limited and conflicting data regarding the role of these measurements in guiding the choice between dose-intensification, switch to another anti-TNF or to another immuno-modulator, and the addition of an immuno-modulator as a combination therapy with the failing anti-TNF. Anti-TNF re-induction after prior drug-holiday is a distinct clinical scenario and scarce evidence suggests re-induction outcome to be dependent on the circumstances when drug-holiday was commenced. Finally, discontinuation of anti-TNF in patients with stable deep clinico-biologic and mucosal remission may be a viable option, as in these carefully selected patients the majority may enjoy long-term remission without the need for continued anti-TNF treatment.