Natalizumab Induction and Maintenance Therapy for Crohn's Disease

Sandborn, William J.; Colombel, Jean Fréd́eric; Enns, R A; Feagan, Brian G.; Hanauer, Stephen B.; Lawrance, Ian C.; Panaccione, Remo; Sanders, Martin; Schreiber, Stefan; Targan, Stephan R.; Deventer, Sander van; Goldblum, R. M.; Despain, Darrin; Hogge, Gary S.; Rutgeerts, Paul

doi:10.1056/nejmoa043335

Cited by 833 publications

(536 citation statements)

References 13 publications

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“…Experimental studies indicated that blockade of activated lympho cyte homing to the inflamed gut might provide a new approach for therapy of intestinal inflammation 51,52 . Subsequently, the anti α4 integrin antibody natalizumab was tested in clinical trials for Crohn's disease therapy to block T cell homing to the inflamed intestine via α4β7 integrins [53][54][55] (FIG. 1).…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

507

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

507

403

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“…Blocking several integrins/ligands in some experimental models has been shown to be required for effective treatment of experimental IBD (24,25). This could explain the therapeutic efficacy of natalizumab (anti-␣ 4 integrin mAb) in CD by inhibiting the shared ␣ 4 integrin moiety of both ␣ 4 ␤ 1 and ␣ 4 ␤ 7 in effector cells (6). Therefore, the ability of CCL25 to trigger not only ␣ 4 ␤ 7 /MAdCAM-1 adhesion (23) but also ␣ 4 ␤ 1 /VCAM-1 could contribute directly to the adhesion, firm arrest, and subsequent transmigration through the vascular endothelium of effector CCR9 ϩ T cells into the SB in CD.…”

Section: Discussionmentioning

confidence: 99%

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Saruta¹,

Yu²,

Avanesyan³

et al. 2007

The Journal of Immunology

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CCL25/CCR9 chemokine ligand/receptor pair has been reported to play an important role in small bowel (SB) immunity and inflammation. We have previously reported an aberrant SB expression of CCL25 in Crohn’s disease (CD) and an increased frequency of CCR9+ T cells in the peripheral blood of patients with SB inflammatory diseases such as CD and celiac disease. In this study, we have characterized the phenotype and effector function of CCR9+ T cells in mucosal lymphoid tissues in CD. We show that CCR9+ T cells isolated from mesenteric lymph nodes (MLN) draining CD SB express a more activated phenotype compared with MLN draining normal SB. Stimulation of CCR9+ T cells isolated from CD SB lamina propria produced more IFN-γ and IL-17 in response to anti-CD3 or IL-12/IL-18 stimulation compared with those isolated from normal SB. The addition of TL1A to the cytokine combination markedly augmented the secretion of IFN-γ, but not IL-17, by CD lamina propria CCR9+ T cells. CCL25 incubation of CD SB lamina propria lymphocytes and MLN lymphocytes increased their adhesion to VCAM-1/Fc in vitro. Finally, the TCRVβ analysis of CCR9+ T cells revealed a diverse TCRVβ repertoire among MLN CCR9+ T cells in patients with SB CD. Our data indicate that CCR9+ T cells in SB CD are proinflammatory and support the rationale for the use of CCR9 antagonists for the treatment of human SB CD.

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“…For other therapeutic groups, frequently included in polypharmacy, it is more difficult to establish the causal relationship with PML since it is not possible to identify the main suspected drug. This issue is very important because early PML cases in natalizumab recipients developed in clinical trials where natalizumab was used in association with interferon or immunosuppressive drugs [31,32]. In order to avoid strong immunosuppression from a drug-drug combination, the use of natalizumab was restricted to monotherapy of relapsing remitting multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

Piccinni

Sacripanti

Poluzzi

et al. 2009

Eur J Clin Pharmacol

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Aim The aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/ or drug immunosuppression in PML occurrence. Methods We searched for drug-induced PML cases in two international spontaneous adverse drug reaction (ADR) report databases, FDA-AERS and WHO-VigiBase. From MEDLINE, we retrieved case reports and case series containing the MESH term "leukoencephalopathy, progressive multifocal/chemically induced". In order to assess the PML-drug relationship, we analysed drug-reaction pairs in terms of the patients' underlying diseases and co-suspected drugs. Results Overall, 214 cases in FDA-AERS, 118 in WHOVigiBase and 140 in MEDLINE were collected. Therapeutic groups more frequently involved in PML cases were monoclonal antibodies (MAbs), conventional immunosuppressive drugs and anti-HIV drugs. The most frequent underlying diseases were lymphoproliferative diseases (28%), autoimmune disorders (20%) and transplants (10%). MAbs were more often reported in cases where they were the only suspected drugs, whereas for the other therapeutic groups, concomitant drugs were reported. ConclusionsWe found a strong relationship between PML and MAbs, especially when used in autoimmune diseases. PML is becoming a crucial issue of MAbs, since they can cause severe ADRs through the imbalance of the immune system. Based on these results, patients treated with MAbs should be carefully monitored for early signs and symptoms of PML.

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Natalizumab Induction and Maintenance Therapy for Crohn's Disease

Cited by 833 publications

References 13 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

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