Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

Colombel, Jean Fréd́eric; Rutgeerts, Paul; Reinisch, Walter; Eßer, Dirk; Wang, Yanxin; Lang, Yinghua; Marano, Colleen; Strauß, Richard; Oddens, B.J.; Feagan, Brian G.; Hanauer, Stephen B.; Lichtenstein, Gary R.; Present, Daniel H.; Sands, Bruce E.; Sandborn, William J.

doi:10.1053/j.gastro.2011.06.054

Cited by 830 publications

(575 citation statements)

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“…As many patients with IBD were either refractory or intolerant to treat ment with the classic agents already discussed, there was an urgent need for the development of more specific novel therapeutic approaches. In this context, anti TNF agents, including infliximab, adalimumab, golimumab and certo lizumab pegol, were introduced into clin ical therapy for IBD 14,[23][24][25][26][27][28][29][30][31][32][33] . For instance, infliximab was shown to be effective for induction and maintenance of remission in both Crohn's disease and ulcerative colitis as well as for treatment of fistulas in Crohn's disease, highlighting the broad relevance of anti TNF therapy 14,24 .…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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“…Tumour necrosis factor alpha (TNF␣) is an important cytokine involved in the pathogenesis of inflammatory bowel disease and targeting this cytokine may be an effective therapy in patients with UC [3]. Infliximab, a chimeric monoclonal antibody to TNF ␣ has been shown to be effective for inducing and maintaining response and remission, inducing mucosal healing and reducing the need for colectomy in patients with moderate-to-severe UC that is refractory to conventional treatment [4][5][6][7][8][9]. However, infliximab is immunogenic and infusion reactions and loss of response related to antibodies to infliximab may be a relevant problem [10].…”

Section: Introductionmentioning

confidence: 99%

Adalimumab in active ulcerative colitis: A “real-life” observational study

Armuzzi¹,

Biancone²,

Daperno³

et al. 2013

Digestive and Liver Disease

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a b s t r a c tBackground and aims: The effectiveness of adalimumab in the treatment of ulcerative colitis is under debate. Although controlled trials have shown that adalimumab is significantly better than placebo, the absolute clinical benefit is modest. We report data on the effectiveness of adalimumab in a cohort of ulcerative colitis patients treated in 22 Italian centres. Methods: All patients with active disease treated with adalimumab were retrospectively reviewed. Coprimary endpoints were clinical remission at weeks 4, 12, 24 and 54. Secondary endpoints were sustained clinical remission, steroid discontinuation, endoscopic remission and need for colectomy. Results: Eighty-eight patients were included. Most patients had received previous infliximab treatment. Clinical remission rates were 17%, 28.4%, 36.4% and 43.2% at 4, 12, 24 and 54 weeks respectively. Twentytwo patients required colectomy. Clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36-19.44; OR 2.63, 95% CI 2.32-14.94, respectively). Previous immunosuppressant use was associated with a lower probability of clinical remission at week 54 (OR 0.67, and with a higher rate of colectomy (HR 9.7, 95% CI 1.46-9.07). Conclusion: In this large "real-life" experience adalimumab appears effective in patients with otherwise medically refractory ulcerative colitis. Patients achieving early remission can expect a better long-term outcome.

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“…Th e introduction of anti-TNF therapies more than a decade ago for the treatment of IBD has transformed management, in particular for those patients with more moderate or severe disease. In addition to showing clinical benefi t in the short and medium term, data are now emerging that these agents can alter the natural history of disease as well reducing hospitalizations and the need for surgery ( 9 ). Nevertheless, widespread use of these agents is limited by factors such as expense and concern over potential adverse events including infection and lymphoma.…”

Section: Biomarkers For Prognosismentioning

confidence: 99%

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

Lichtenstein¹,

McGovern²

2016

Am J Gastroenterol Suppl

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Biomarkers, radiology fi ndings, and endoscopic studies, together with clinical assessment of patients with infl ammatory bowel disease, can be used to help determine prognosis, assess disease activity, and increasingly to inform treatment decision-making. This article reviews the current "state of the science" regarding the multitude of different tests that can be performed and how these can be used in the clinic to guide management. Initially, when patients present with symptoms suggestive of infl ammatory bowel disease (IBD), standard endoscopic studies and radiographic studies should be performed and the use of combinations of serologic and fecal markers may additionally be incorporated into patient assessment. Once the patient has a formal diagnosis, prognosis should be assessed and serologic evaluation may be used, but in conjunction with endoscopic and radiographic studies. Within the context of evaluating clinical predictors of disease (e.g., disease location, nutritional status, routine blood tests), early mucosal healing has been linked to better outcomes, and failure to heal the mucosa has been associated with poorer outcomes. Evaluation of response to therapy can be approximated with the use of biomarkers (e.g., C-reactive protein, fecal calprotectin, lactoferrin), and therapeutic drug monitoring has enabled us to assess levels of drug metabolites, drug levels, and antidrug antibodies to guide the ongoing management. Although there is not yet universal adoption of biomarkers to determine treatment choices (e.g., the use of anti-tumor necrosis factor therapy), biomarkers have enabled us to "fi ne tune" treatment of some patients with IBD. Establishing mechanisms of communicating these risks/benefi ts to patients will be a considerable challenge and remains a priority area of research.

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Early Mucosal Healing With Infliximab Is Associated With Improved Long-term Clinical Outcomes in Ulcerative Colitis

Cited by 830 publications

References 20 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Adalimumab in active ulcerative colitis: A “real-life” observational study

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

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