TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction

doi: 10.3389/fimmu.2014.00018 TWEAK/Fn14 signaling axis mediates skeletal muscle atrophy and metabolic dysfunctio

Vedolizumab: an α4β7 integrin antagonist for ulcerative colitis and Crohn’s disease

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic, relapsing inflammatory bowel diseases associated with significant morbidity. Conventional therapies for these diseases include corticosteroids, aminosalicylates, immunomodulators, and monoclonal antibodies. Over the years tumor necrosis factor (TNF)-α antagonists alone or in combination with other therapies have emerged as the cornerstone of treatment for induction and maintenance of remission of moderate to severe UC and CD. Unfortunately, some patients with moderate to severe UC and CD are unable to attain or maintain remission with TNF-α antagonist treatment. Vedolizumab, a humanized monoclonal antibody, is the first integrin receptor antagonist approved that selectively antagonizes α4β7 gastrointestinal integrin receptors. US Food and Drug Administration approval is for treatment of patients with moderate to severe active UC and CD who have inadequate response with, lost response to, or are intolerant to a TNF-α antagonist or an immunomodulator; or have inadequate response with, are intolerant to, or demonstrate dependence on corticosteroids. When administered according to approved dosing in patients with moderate to severe CD and UC, vedolizumab induces clinical response rates up to 31.4% and 47.1% at week 6, and clinical remission rates up to 39% and 41.8% at week 52, respectively. Serious adverse events reported with vedolizumab include serious infections, malignancies, and anaphylaxis. Since vedolizumab is gastrointestinal selective, to date, it has not shown evidence of causing progressive multifocal leukoencephalopathy; however, postmarketing studies monitoring for this adverse effect are ongoing. Further assessment of vedolizumab earlier in the course of these diseases and in combination with other therapies is warranted

What is the risk of progressive multifocal leukoencephalopathy in patients with ulcerative colitis or Crohn’s Disease treated with vedolizumab?

Background: Progressive multifocal leukoencephalopathy is a serious condition linked to certain diseases and immunosuppressant therapies, including the α4 integrin antagonist natalizumab. No cases have been reported to date with vedolizumab, a selective antagonist of the α4β7 integrin expressed on gut-homing lymphocytes. This analysis aimed to describe the current and future expected occurrence of progressive multifocal leukoencephalopathy with vedolizumab use, were the risk the same as in other populations in which this disease has been studied. Methods: The expected number of vedolizumab-associated progressive multifocal leukoencephalopathy cases was estimated up to May 19, 2016 and modelled up to 2034. These estimates were based on the cumulative exposure to the drug, assuming an equivalent risk to that of patients treated with natalizumab or those from other reference populations where progressive multifocal leukoencephalopathy has been examined. Future cases were modelled based on similar risks and projected sales. Results: The cumulative vedolizumab exposure was estimated at 54,619 patient-years, with a 95% confidence interval of 0.0–6.75 cases per 100,000 patient-years. An estimated 30.2 (95% confidence interval 19.4–40.9) cases of progressive multifocal leukoencephalopathy would have occurred if vedolizumab had the same risk as that of natalizumab. There would be a 50% chance of the first case occurring by 2018, assuming an equivalent risk to the general population. Conclusions: These analyses indicate the risk of progressive multifocal leukoencephalopathy with vedolizumab is small, and unlikely to be above 6.75 cases per 100,000 patient-years