Review article: Causative factors and clinical management of patients with Crohn’s disease who lose response to anti-TNFφ therapeutics (original) (raw)
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Digestive and Liver Disease, 2016
Background: Anti-TNF treatment is effective for Crohn's disease (CD); however, some patients did not achieve remission with these drugs. Aims: To evaluate the short-term effectiveness of a second anti-TNF in CD patients who did not achieve remission with the first one and to assess its durability. Methods: Patients who did not achieve remission with their first anti-TNF were included. The shortterm response of the second anti-TNF was assessed, the long-term response was evaluated in patients who achieved remission (Kaplan-Meier). Cox-regression was performed to identify predictors of loss of efficacy.
Do not assume symptoms indicate failure of anti-tumor necrosis factor therapy in Crohn's disease
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2011
It is a challenge to monitor patients with Crohn's disease who remain symptomatic despite anti-tumor necrosis factor therapy. Clinicians must use a systematic approach for each patient and obtain objective evidence about disease activity and response to therapy. Alternate etiologies for symptoms should be sought and treated, if found. Active Crohn's disease despite therapy requires reassessment and adjustments to management plans.
Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology
Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease (IBD) which affects any site of the gastrointestinal tract and occasionally extraintestinal organs. The natural history of CD varies remarkably but a considerable proportion of patients develop complications leading to hospitalizations and surgeries, impaired quality of life, and disability. In these patients, effective medical therapy should aim beyond control of clinical symptoms to include induction and maintenance of steroid-free clinical and serological remission and mucosal healing, as this has shown to reduce complications, hospitalizations and surgeries, and to decrease the risk of colorectal cancer, at least in the short term. This therapeutic goal can be achieved in a considerable proportion of patients with anti-tumor necrosis factor (TNF)-α agents if applied early in the disease course. Clinical recommendations from a panel of Greek IBD experts are herein provided, regarding the clinical profiles...
Outcomes of Anti-TNF Treatment in Crohn’s Disease: A Real-Life, Tertiary Center Experience
Journal of Enterocolitis, 2022
Objective: The main treatment option for Crohn's Disease is anti-tumor necrosis factor agents. In this study, we assess the real-life experience of anti-tumor necrosis factor treatment in a tertiary center. Methods: We enrolled the patients retrospectively who were followed up at our Inflammatory bowel disease-specific gastroenterology outpatient clinic between October 2006 and April 2019. We collected demographic and clinical data from the electronic hospital database and hardcopy of patient files. The primary outcomes of this study are short-term and long-term efficacy. Secondary outcomes are the safety of treatments and indications of anti-tumor necrosis factor initiation. Results: A total of 870 Crohn's disease patients were screened, 236 were exposed to anti-tumor necrosis factor, and 200 patients were included for the final analysis. The median follow-up period of anti-tumor necrosis factor treatment was 55 months (range: 4-168). A total of 133 patients received infliximab, 97 received adalimumab, and 11 received certolizumab as first-, second-, or third-line treatment. In total, 6 patients (4.2%) were primary unresponsive and 15 (10.6%) patients were secondary unresponsive to infliximab; 3 patients (2.8%) were primary unresponsive and 14 patients (13.3%) were secondary unresponsive to adalimumab; and 2 (18%) patients were primary unresponsive and 1 (9%) patient was secondary unresponsive to certolizumab. The most common indication of anti-tumor necrosis factor treatment was fistula formation (47.7%, n = 87). However, 63 (50.0%) fistulizing patients had no response to anti-tumor necrosis factor treatment. Conclusion: Two-thirds of the patients had treatment response, and no significant difference was seen between agents. Half of the patients has fistulizing disease and 50% of them were non-responders.
The Lancet Gastroenterology & Hepatology
Background Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. Methods The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14 ,non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. Findings We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23•8%, 95% CI 21•4-26•2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63•1%, 60•3-65•8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7•8%, 6•6-9•2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0•35 [95% CI 0•20-0•62], p=0•00038; adalimumab: 0•13 [0•06-0•28], p<0•0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12•4% [95% CI 6•9-19•9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0•29 [0•16-0•52] for infliximab; 0•03 [0•01-0•12] for adalimumab; p<0•0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62•8% (95% CI 59•0-66•3) for infliximab and 28•5% (24•0-32•7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immuno-modulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0•39 [95% CI 0•32-0•46] for infliximab; 0•44 [0•31-0•64] for adalimumab; p<0•0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0•56 [95% CI 0•38-0•83], p=0•004). Interpretation Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes.
Optimizing the Use of Tumour Necrosis Factor Inhibitors in Crohnʼs Disease
Drugs, 2010
Crohn's disease is a chronic, disabling, inflammatory condition of the gastrointestinal tract that has a segmental distribution and can affect the entire gastrointestinal tract. Treatment of patients with Crohn's disease represents a difficult challenge to physicians. Conventional therapy includes corticosteroids and immunosuppressants. Corticosteroids are highly effective for inducing response and remission, but the results in the long-term are disappointing and are associated with serious adverse events. Immunosuppressants are effective, but have a slow onset of action and are associated with intolerance and adverse events. In the last decade, as a result of a better understanding of the immunopathology of inflammatory bowel disease, novel therapeutic agents have been developed to target crucial components of the inflammatory cascade. Tumour necrosis factor (TNF) inhibitors (infliximab, adalimumab and certolizumab pegol) offer an effective alternative therapy, and are widely used in clinical practice for the management of Crohn's disease and ulcerative colitis. This article focuses on the latest evidence-based data on clinical effectiveness, mucosal healing, immunogenicity, dose optimization for induction and maintenance of response and remission, and step-up versus top-down approaches of the available TNF inhibitors for the treatment of Crohn's disease.
Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease
Alimentary Pharmacology & Therapeutics, 2019
Background: Biological therapy is currently widely used to treat IBD. Infliximab, adalimumab and golimumab are currently licensed anti-TNF therapies. Biosimilar anti-TNF monoclonal antibodies are increasingly used. Anti-TNF therapies are widely used and their adverse effects are well characterised, and may cause significant morbidity and mortality in a small proportion of exposed patients. Gastroenterologists need to understand the mechanisms for these effects, recognise these swiftly and manage such events appropriately. Aim: To cover the range of potential adverse reactions as a result of biologic therapy and specifically management of these events. Methods: A Medline and Pubmed search was undertaken. Search terms included were "anti-TNF," "infliximab" or "adalimumab" or "golimumab" combined with the keywords "ulcerative colitis" or "Crohn's disease" or "inflammatory bowel disease" and then narrowed to articles containing the keywords "complications," "side effects" or "adverse events" or "safety profile." International guidelines were also reviewed where relevant. Results: Adverse events discussed in this review include infusion reactions, blood disorders and infections (including bacterial, viral, fungal and opportunistic infections) as well as autoimmune, dermatological disorders, cardiac and neurological conditions. Malignancies including solid organ, haematological and those linked to viral disease are discussed. Conclusions: Anti-TNF therapy has wide-ranging effects on the immune system resulting in a spectrum of potential adverse events in a small proportion of patients. Research advances are improving the understanding, recognition and management of these adverse events. The Handling Editor for this article was Dr Nicholas Kennedy, and this uncommissioned review was accepted for publication after full peer-review.
Inflammatory bowel diseases, 2016
Although biological agents targeting tumor necrosis factor (TNF) alpha are effective in the management of Crohn's disease (CD), use of anti-TNF agents is often delayed until after failure of other treatment modalities, resulting in potentially long delays between diagnosis and initiation of infliximab or adalimumab. We aim to determine if early treatment with anti-TNF agents reduces the rate of surgical resection and clinical secondary loss of response in CD patients. A retrospective cohort study was conducted evaluating CD outpatients who were primary responders to anti-TNF therapy, on a maintenance regimen with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first dose of anti-TNF therapy; early initiation was defined as starting anti-TNF therapy within 2 years of diagnosis. The primary outcome was occurrence of surgical resection or clinical secondary loss of response requiring dose escalation. Kaplan-Meier analysis was used to assess time to t...