The Beneficial Role Of Tnf
Soon after the identification of TNF and production of recombinant TNF, it was recognized that the biological effects of TNF may be both injurious and beneficial. TNF can have a direct cytostatic and cytotoxic effect on human tumor cells, as well as a variety of immunomodulatory effects on various immune effector cells, including neutrophils, macrophages, and T cells. It can have a number of anti-infective and metabolic effects .
Today, in the era of anti-TNF drugs, the beneficial role of TNF is often in the shadow and is highlighted only after the appearance of a new adverse effect of anti-TNF drugs in clinical use.
Experimental studies have shown that TNF has important role in maintaining intestinal integrity . If infection or injury occurs, TNF is rapidly released to promote the acute-phase inflammatory response and to trigger the localized accumulation of leukocytes. Endothelial cells respond to TNF by releasing chemokines and adhesion molecules . Collectively, these solubles and cell surface molecules lead to the recruitment of distinct populations of leukocytes to sites of infection/injury to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair. Indirectly, TNF also contribute to increased local blood flow and vascular permeability and regulation of coagulation. TNF increases mediators such as prostaglandins and platelet-activating factor .
Factors Associated With Clinical And Endoscopic Remission At Week 52
According to logistic regression analysis , variables associated with clinical remission at week 52 were age , total Mayo score at baseline , no prior exposure to biological therapy , use of IFX , clinical response at week 26 and endoscopic remission at week 26 .
Table 5 Univariate logistic regression model with associated factors for clinical and endoscopic remission at week 52 of treatment in UC patients
Variables associated with endoscopic remission at week 52 were no prior exposure to biological therapy , clinical response at week 8 , clinical response at week 26 and endoscopic remission at week 26 . The type of anti-TNF used was not associated with endoscopic remission at week 52.
According to the KaplanMeier survival curve, clinical remission at week 52 was not different between biologic naïve or biologic exposed patients , Fig. A. On the other hand, biologic naïve patients showed a lower probability of loss of response as compared to biologic exposed patients , Fig. B. Colectomy rates were not different between the groups, Fig. C.
Fig. 3
KaplanMeier survival curves showing the relationship between clinical remission at week 52 , loss of response , and colectomy according to previous exposure to biologic therapy. Biologic naïve patients showed lower probability of loss of response as compared to biologic exposed patients
How You Take Them
Some TNF inhibitors, including Cimzia, Humira, Enbrel, Erelzi, and Simponi, are given as shots under the skin. You’ll get your first one or two at your doctor’s office then your doctor or a nurse will show you how to give them to yourself. Once you get comfortable with that, pre-filled shots can be shipped to your home.
Every 1 to 4 weeks, you’ll inject your TNF inhibitor under the skin of your thigh or abdomen. You can use a different spot each time.
Remicade, Inflectra, and Simponi Aria, a version of Simponi, are given as infusions at a clinic or your doctor’s office. While you lie still, it’s slowly dripped into your vein through a tube. For Remicade, each session can take around 2 hours, and you’ll need treatment every 4 to 8 weeks. With Simponi Aria, the sessions last 30 minutes. After two starter doses one month apart, they’re given once every 8 weeks.
Your doctor may have you use a TNF inhibitor in combination with other drugs, such as methotrexate, prednisone, hydroxychloroquine , leflunomide , or sulfasalazine .
You may have to take these medications for a long time. If you go off them because you feel better, your inflammation can come back. Some people can cut down their dose instead of stopping the drugs altogether. Always take your medication as your doctor prescribes.
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Mechanisms Of Resistance To Anti
Recently, the concept that changes in the composition of immune cell infiltrates in response to therapeutic pressure lead to molecular resistance to the applied drug has been introduced to the IBD filed . An improved understanding of molecular resistance is essential to optimize personalized treatment in IBD. First studies have indicated mechanisms that drive primary resistance to biological therapy in IBD.
What Are Biologics For Ulcerative Colitis
Biologics are medications that doctors use to treat chronic inflammatory conditions such as inflammatory bowel disease . Ulcerative colitis is one type of IBD.
These laboratory-made antibodies are targeted to block specific proteins responsible for the inflammation that drives ulcerative colitis. This makes biologics different from medications such as corticosteroids, which may cause more severe side effects.
The Food and Drug Administration has approved the following biologics to treat moderate-to-severe ulcerative colitis:
- anti-tumor necrosis factor agents, including:
- infliximab
- adalimumab
- golimumab
The FDA approved the biosimilars of infliximab and adalimumab. As their name suggests, biosimilars are very similar to the originally approved biologics but may be more cost effective.
A person may receive biologics as an injection, as an infusion through an intravenous line, or by mouth.
The method of use, dosage, and frequency varies from one type of biologic to another.
Doctors typically prescribe an anti-TNF agent before they prescribe other types of biologics for moderate-to-severe ulcerative colitis. This is because anti-TNF medications are the most studied treatments.
Doctors may prescribe another type of biologic or a JAK inhibitor if the anti-TNF agent:
JAK inhibitors can include
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Beyond Tnf Inhibitors In Ulcerative Colitis: Promising Data
Nicola M. Parry, DVM
The availability of tumor necrosis factor inhibitors changed treatment for many patients with ulcerative colitis , but not everyone responds to these drugs, and even among those who do so initially, response often diminishes over time. Now, two trials, published online September 26 in the New England Journal of Medicine, show that many of these patients do respond to other types of biologic therapy.
In the head-to-head VARSITY trial, “vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement,” write Bruce E. Sands, MD, from the Icahn School of Medicine at Mount Sinai, New York City, and colleagues in the VARSITY study group.
In the UNIFI trial, “ustekinumab was more effective than placebo for inducing and maintaining remission,” write Sands and colleagues in the UNIFI study group.
The findings are potentially important for long-term outcomes, writes Richard J. Farrell, MD, from Connolly Hospital and the Royal College of Surgeons in Ireland, Dublin, in an accompanying editorial.
“Despite an improving treatment landscape, long-term rates of colectomy for ulcerative colitis have not declined over a 10-year period, a fact that highlights the need for new biologic therapies and strategies,” he writes.
Adverse Effects Of Biological Therapy
The randomized, controlled trials have demonstrated a generally favorable safety profile for biological agents however, a few patients do experience side-effects and biological agents have been occasionally associated with severesometimes life threateningadverse effects necessitating careful monitoring of therapy . Many of these adverse effects are related to the immunosuppressive effects of biological agents. These are discussed below.
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How Do Biological Medications For Ibd Affect The Eyes
Biological medications are drugs produced using living cells. The most common biologics for IBD fall within a class of drugs called tumor necrosis factor -alpha inhibitors. TNF-alpha inhibitors help to block inflammation from the immune system, which makes them effective at treating the symptoms of Crohns and ulcerative colitis.
Typical TNF-alpha inhibitors include:
Many MyCrohnsAndColitisTeam members also report having taken another medication called ustekinumab . This is not a TNF-alpha inhibitor but works to reduce inflammation in people with IBD.
People who take TNF-alpha inhibitors typically tolerate them well regarding side effects. Eye complications from TNF-alpha inhibitors are rare and include:
Although someone with IBD can develop uveitis after taking a TNF-alpha inhibitor, uveitis is also linked to IBD itself. Taking a TNF-alpha inhibitor can help decrease the signs and symptoms of uveitis by treating IBD.
Eye complications associated with ustekinumab are rare. When they occur, they include:
- Blurry vision
- Light sensitivity
- Seeing halos around lights
If youre taking a steroid or biologic medication for IBD and experience changes to your vision, you should tell your doctor or health care provider as soon as possible. This allows the doctor to treat the visual problem promptly and/or refer you to a specialist if needed.
Indications For Tnf Inhibitors
Crohns Disease
European consensus guidelines and the American College of Gastroenterology guidelines list similar indications for TNF inhibitors for CD, which include
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steroid refractory or dependant disease,
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immunomodulator refractory disease,
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severely active disease with adverse prognostic factors, and
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fistulizing disease.
Negative prognostic factors for CD include disease onset below age 40 years, perianal disease, active smoking, prior intestinal surgical resection, need for steroids at diagnosis, stricturing disease, and small intestinal disease .
Ulcerative Colitis
Indications for TNF inhibitors in UC include
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steroid refractory severe colitis,
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oral steroid refractory disease, and
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immunomodulator refractory disease.
Negative prognostic factors for UC include disease onset at the age of < 16 years, C-reactive protein > 10 mg/L after 1 year of extensive colitis, and admission for acute severe colitis .
Combination Therapy of anti-TNF Agents with Immunomodulators
Contraindications and Precaution
The relative or absolute contraindications of TNF inhibitors can be summarized by the acronym STOIC: Sepsis/abscess, Tuberculosis, Optic neuritis , Infusion reaction , Cancer/lymphoma and Congestive heart failure .
Prebiological Treatment Screening
Administration of IFX
Infusion Protocols
Subcutaneous IFX
Monitoring Safety and Managing Adverse Effects
Infusion Reactions and Premedication
Table 3.
Management of IFX infusion reactions
Infectious Complications
Malignancy
Surgery
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Study Design And Patients
This was a single-centre retrospective study conducted between November 2005 and December 2020. Patients diagnosed with CD or UC aged> 18 years and managed at Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, were eligible . Patients had moderately to severely active disease, defined by a Mayo score of 612 for UC and a Crohns disease activity index of 220 or higher for CD. They had also received at least one injection of infliximab, adalimumab, or golimumab as induction treatment, and anti-TNF therapy had been discontinued as the first-line treatment due to a primary non-response, secondary loss of response, occurrence of side effects or malignant tumours, or pregnancy. Those who had not previously used an anti-TNF agent or had been followed-up for< 16 weeks were excluded.
Il7r Depending Signaling Pathway
Another study elucidated heightened expression of the IL7R and the IL-7 dependent signaling pathway in the inflamed colon of IBD patients non-responsive to anti-TNF therapy. The IL-7R signaling specifically regulates effector but not regulatory T cell homing to the gut by controlling alpha4 and beta7 integrin expression, thereby implicating blockade of the IL-7R as a novel therapeutic option in IBD .
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A Link Between Tnf And Ibd
The first evidence showing a link between TNF and IBD were publications reporting that patients with IBD have increased levels of TNF in serum, stool, or mucosal biopsy specimens . However, the initial hopes for the use of TNF as a marker of IBD have waned when it was recognized that TNF can be increased also during infectious colitis or TNF may even not be increased in patients with IBD or TNF can be reduced in response to certain medication such as cyclosporine A . Nevertheless, a published reports about successful treatment of CD patients with TNF chimeric monoclonal antibodies established clear association of TNF involvement in the pathogenesis of IBD and caused extensive investigation of TNF role in IBD and production of various genetic models, including transgenic mice with persistent TNF overproduction in various tissues.
Study Setting And Data Sources
We conducted a population-based study in adult patients with IBD residing in Ontario between 1 July 1995 and 31 March 2012 using provincial health administrative data. Ontario is a geographically and ethnically diverse province of Canada comprising more than 13 500 000 residents and close to 100000 individuals with IBD. The Ontario government covers 100% of the costs of medically necessary healthcare services for all its citizens, including hospital-based care, ambulatory physician visits and procedures and chronic care services. It also subsidises the cost of select prescription drugs for individuals aged 65 years or older and those requiring social assistance, through the Ontario Drug Benefits Programme, as well as the costs of expensive drugs, such as biologic therapies, on a case-by-case basis through the ODB Exceptional Access Programme. Across Canada, 41.8% of prescribed drug spending is paid for by provincial healthcare plans.
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Vedolizumab Bests Adalimumab In Trial
VARSITY was a phase 3b, double-blind, double-dummy, randomized, controlled trial that compared the efficacy and safety of intravenous infusions of vedolizumab with subcutaneous injections of adalimumab in patients with moderate to severe active UC.
The trial took place across 245 sites in 34 countries. It included 769 adults aged 18 to 85 years who were randomly assigned to receive either vedolizumab IV plus subcutaneous injections of placebo, or subcutaneous injections of adalimumab and placebo IV.
The study’s primary endpoint was clinical remission at week 52 secondary endpoints were endoscopic improvement and corticosteroid-free remission at week 52.
The results showed that after 52 weeks of treatment, significantly more patients in the vedolizumab group than in the adalimumab group had achieved clinical remission , which was the study’s primary endpoint.
In addition, more patients in the vedolizumab group experienced mucosal healing compared with those in the adalimumab group .
“Few differences were observed between the trial groups in terms of the most commonly reported adverse events ,” write Sands and colleagues.
AEs were reported in 62.7% of patients in the vedolizumab group and in 69.2% of those in the adalimumab group. Serious AEs occurred in 11.0% and 13.7% of patients in each group, respectively.
Exposure-adjusted rates of infection and serious infection were lower among patients who received vedolizumab than among those who received adalimumab.
Different Types Of Tnf
Genetic studies have shown that there are different types of TNF, and TNF is actually considered a “superfamily.” Various types of TNF have been associated with particular autoimmune diseases, cancers, and diabetes. Finding the types of TNF-associated with particular conditions can help in developing drugs to treat those diseases.
Not everyone with IBD responds to the same drugs in the same way. This could be, and it is now thought to be the case by experts, that there are many subtypes of IBD. TNF may play a role in this too, because some people with IBD respond very well to anti-TNF blocker drugs, while other people do not. The genotype of a particular patient’s TNF may be associated with a greater or a lesser response to a particular anti-TNF drug. This is an emerging area of research, and there is still much more to be understood about TNF before it can be applied to patient care.
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Jak Inhibitor Helped When Biologic Didn’t
byDiana Swift, Contributing Writer, MedPage Today March 12, 2021
Treatment with tofacitinib proved to be rapidly effective for moderate-to-severe ulcerative colitis , even in patients who previously failed tumor necrosis factor inhibition, post hoc analysis of trial data indicated.
While the oral small-molecule JAK inhibitor had greater efficacy than placebo for both induction and maintenance of remission, rates of herpes zoster were numerically higher in tofacitinib recipients, regardless of previous response to TNF inhibition, reported William Sandborn, MD, of the University of California San Diego.
TNF inhibitor failure has been suggested as a predictor of poor prognosis in UC. Patients refractory to this therapy may be more challenging to treat, and therefore have an unmet need for alternative therapies.
However, “our findings show that tofacitinib induces and maintains clinical response, endoscopic improvement, and remission in patients with and without prior TNF failure,” the team wrote in Clinical Gastroenterology and Hepatology.
Earlier this year, Sandborn’s group reported on the efficacy of tofacitinib versus certain biologics in UC. The current analysis involved participants in the OCTAVE Induction, Sustain, and Open trials. The clinical studies and this follow-up analysis were supported by tofacitinib’s manufacturer, Pfizer.
The Cohorts
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Diana Swift is a freelance medical journalist based in Toronto.
Disclosures
Primary Source
Biological Therapy For Mucosal Healing In Ulcerative Colitis
Although the main focus of treatment of patients with UC has traditionally been the alleviation of symptoms by inducing and maintaining symptomatic remission, there is increasing evidence to suggest that achieving mucosal healing and reduction in endoscopic disease activity may be as critical as improvement in symptoms in optimizing long-term outcomes . Indeed, mucosal healing has been shown to correlate with better long-term remission rates, fewer disease-related complications and better quality of life for patients .
The efficacy of biological agents in reversing the tissue damage associated with inflammation has been well studied. The efficacy of infliximab in mucosal healing was assessed during the ACT1 and ACT2 trials . Mucosal healing was defined as a Mayo endoscopic subscore of 1. The infliximab group exhibited significantly higher rates of mucosal healing than the placebo group at weeks 8 and 30 in both trials and at week 54 in the ACT1 trial . Similarly, during the ULTRA2 trial, which assessed the efficacy of adalimumab, mucosal healing rates were higher in the treatment group than those in the placebo group both at week 8 and week 52 . Higher rates of mucosal healing were also seen in patients treated with golimumab than with placebo at weeks 6 and 54 in the PURSUIT-SC and PURSUIT-M trials, respectively .
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