Use Of Tumor Necrosis Factor Antagonists Research Articles

Comparative Outcomes and Safety of Vedolizumab vs Tumor Necrosis Factor Antagonists for Older Adults With Inflammatory Bowel Diseases

Observational comparative effectiveness studies can inform the positioning of biologic therapies for older patients with inflammatory bowel disease (IBD) who are underrepresented in clinical trials. To compare the effectiveness and safety of vedolizumab vs tumor necrosis factor (TNF) for older patients with IBD. This active comparator, new-user design, comparative effectiveness study was conducted between January 1, 2005, and December 31, 2018, among 754 older patients (aged ≥50 years) with IBD from the Danish National Patient Register. The mean follow-up after treatment initiation took place at 32 to 40 weeks. Statistical analysis was performed from February 1 to April 27, 2022. Treatment with vedolizumab or TNF antagonists. The primary effectiveness outcome was treatment failure, defined as the composite risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with biologic therapy. Secondary effectiveness outcomes were time to each individual component of the composite effectiveness outcome. The primary safety outcome was the risk of serious infections, defined as infections requiring hospitalization. A 1:1 propensity score-matched analysis was conducted, accounting for patient-, disease-, and treatment-associated factors. The study compared 377 older patients with IBD with incident use of vedolizumab (202 women [53.6%]; mean [SD] age, 61.2 [8.3] years; 177 [46.9%] with Crohn disease) vs 377 patients with incident use of TNF antagonists (206 women [54.6%]; mean [SD] age, 61.3 [8.1] years; 182 [48.3%] with Crohn disease). Overall, vedolizumab was associated with an increased risk of treatment failure compared with TNF antagonists (1-year risk, 45.4% vs 34.7%; adjusted hazard ratio [HR], 1.31; 95% CI, 1.02-1.69), including higher risk of IBD-related hospitalization (1-year risk, 27.8% vs 16.3%; adjusted HR, 1.48; 95% CI, 1.03-2.15) and IBD-related major abdominal surgery (1-year risk, 21.3% vs 8.0%; adjusted HR, 2.39; 95% CI, 1.45-3.94). In subgroup analysis by IBD phenotype, among patients with Crohn disease, vedolizumab was associated with a 77% higher risk of treatment failure (adjusted HR, 1.77; 95% CI, 1.21-2.58), while no difference in risk of treatment failure was seen among patients with ulcerative colitis (adjusted HR, 1.04; 95% CI, 0.75-1.43; P = .03 for interaction). There was no significant difference in the risk of serious infections, overall (1-year risk, 8.2% vs 8.7%; adjusted HR, 1.04; 95% CI, 0.58-1.85) and by IBD phenotype. In this comparative effectiveness study of older patients with IBD, vedolizumab was associated with a higher risk of treatment failure compared with TNF antagonists, particularly among patients with Crohn disease, without offering a significant safety advantage.

Serial Magnetic Resonance Imaging for Monitoring Medical Therapy Effects in Crohn’s Disease

Tumor necrosis factor (TNF) antagonists can induce mucosal healing in patients with Crohn's disease (CD), but the effects on transmural inflammation and stenotic lesions are largely unknown. We performed a retrospective study in 50 patients (54% female, median age 37 yr) with CD who had undergone serial magnetic resonance imaging (MRI) examinations while receiving infliximab or adalimumab. Patients were grouped as clinical responders or nonresponders based on physician's assessment, laboratory, and endoscopic appearance. MRI scoring was performed by 2 radiologists in consensus blinded to clinical data using a validated MRI scoring system. In total, 64 lesions on MRI were identified for analysis. Analyses were performed using paired t test and Wilcoxon rank test. During anti-TNF treatment, MRI inflammation scores improved in 29 of 64 lesions (45.3%), remained unchanged in 18 of 64 lesions (28.1%), or deteriorated in 17 of 64 lesions (26.6%) over time. In the anti-TNF responder group, the mean intestinal inflammation score of all lesions improved from 5.19 to 3.12 (P < 0.0001). The mean inflammation scores in stenotic lesions in anti-TNF responders also improved significantly, from 6.33 to 4.58 (P = 0.01). In contrast, the mean inflammation scores did not change significantly (5.55-5.92, P = 0.49) in nonresponders. Diagnostic accuracy of anti-TNF response on MRI was 68%. Improved inflammatory activity on serial MRI scans was observed in patients with clinical response to medical therapy with anti-TNF agents in luminal CD. MRI can be used as a complementary approach to measure transmural inflammation in patients with CD and guide the optimal use of TNF antagonists in daily clinical practice.

Time‐dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis

To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long-Term Safety (REAL) database. We analyzed 727 RA patients who had started either infliximab or etanercept (the anti-TNF group; 1,480.1 patient-years [PY]) and 571 RA patients who had started conventional nonbiologic disease-modifying antirheumatic drugs (the unexposed group; 1,104.1 PY) at the time of enrollment in the REAL. We assessed the occurrence of SIs within a 3-year observation period, including the period after switching to other TNF antagonists, and all SIs, unlimited to the first one in each patient as reported in other studies, to evaluate the real safety of TNF antagonists in daily practice. The incidence rate of SIs per 100 PY was 5.54 (95% confidence interval [95% CI] 4.44-6.84) in the anti-TNF group and 2.72 (95% CI 1.87-3.83) in the unexposed group. Poisson regression analysis revealed that the relative risk (RR) of continuous use of TNF antagonists for SIs after adjusting for baseline and time-dependent covariates was significantly elevated both overall (1.97, 95% CI 1.25-3.19) and for the first year (2.40, 95% CI 1.20-5.03), but not for the second and third years combined (1.38, 95% CI 0.80-2.43). The adjusted RR for SIs of etanercept compared to infliximab was not significantly elevated. Continuous anti-TNF therapy was significantly associated with increased risks for developing SIs during, but not after, the first year.

Fibrotic and Sclerotic Manifestations of Chronic Graft-versus-Host Disease

Chronic graft versus host disease (cGVHD) is a common cause of morbidity and mortality following allogeneic stem cell transplant (HCT), with approximately 50-60% of long-term HCT survivors developing one or more manifestations of the disorder. While acute GVHD is typically limited to skin, liver and gastrointestinal involvement, virtually every organ is at risk for the development of cGVHD. Though the pathophysiology of cGVHD remains poorly understood, some of the most severe organ manifestations are linked by end organ fibrosis. In particular, fibrotic cutaneous and bronchiolar changes, resulting in scleroderma-like changes and bronchiolitis obliterans syndrome (BOS), respectively, are two of the most devastating outcomes for these patients. Both sclerotic GVHD (ScGVHD) and BOS have been reported in 5 to 15% of patients with cGVHD (1, 2)ENREF 1. Unfortunately, standard treatment for cGVHD has not changed significantly in the past 30 years, and relies heavily on the use of agents that reduce the activity of alloreactive T-cells. Many of the manifestations of cGVHD however, share clinical characteristics seen in non-transplant conditions, including systemic sclerosis or pulmonary fibrosis. Thus, understanding the pathophysiology underlying these related conditions may help identify potential mechanisms and ultimately new therapeutic options for patients with cGVHD. Tyrosine kinase inhibitors (TKIs) have been shown to inhibit two different profibrotic pathways (transforming growth factor β [TGF-β] and platelet-derived growth factor [PDGF]) in various mouse models of fibrotic disease, and offer a possible novel treatment approach for cGVHD patients suffering from severe sclerosis (3). Likewise, overexpression of tumor necrosis factor (TNF)-α has been shown to induce fibrogenesis in experimental hepatocellular disease (4), and has been linked with human scleroderma-associated interstitial pulmonary fibrosis (5) and profibrotic responses in human osteoarthritic hip joint fibroblasts (6). The use of TNF antagonists has been examined in some clinical situations associated with fibrosis (7, 8), suggesting they may also be of some benefit to patients with cGVHD; however, this must first be prospectively tested.

Recommendations for the treatment of Crohnʼs disease with tumor necrosis factor antagonists: An expert consensus report

Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists. Infliximab and adalimumab are approved as second-line treatments for severe, active CD. Certolizumab pegol is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe, active CD. Data from trials of infliximab suggest that high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) may benefit from earlier use of this drug. A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of TNF antagonists. At the time of this survey, infliximab was the only TNF antagonist approved for the treatment of CD in Europe, Canada, and Australia. An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated. The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals, and form a rationale for using TNF antagonists in CD patients. Control of inflammation and induction of mucosal healing were considered essential for bowel preservation. Consensus areas: 1) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 2) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 3) benefits of infliximab in relation to mucosal healing, bowel preservation, and clinical remission increase when therapy is initiated earlier. Treatment with TNF antagonists helps preserve the bowel in CD patients.

The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: A systematic review and meta-analysis of randomized controlled trials

There is a need to better understand the safety of tumor necrosis factor (TNF) inhibitors in patients with psoriatic disease in whom TNF inhibitors are frequently used as monotherapy. We sought to examine the risks of infection and malignancy with the use of TNF antagonists in adult patients with psoriatic disease. We conducted a systematic search for trials of TNF antagonists for adults with plaque psoriasis and psoriatic arthritis. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, and certolizumab for the treatment of plaque psoriasis and psoriatic arthritis. Twenty of 820 identified studies with a total of 6810 patients were included. Results were calculated using fixed effects models and reported as pooled odds ratios. Odds ratios for overall infection and serious infection over a mean of 17.8 weeks were 1.18 (95% confidence interval [CI] 1.05-1.33) and 0.70 (95% CI 0.40-1.21), respectively. When adjusting for patient-years, the incidence rate ratio for overall infection was 1.01 (95% CI 0.92-1.11). The odds ratio for malignancy was 1.48 (95% CI 0.71-3.09) and 1.26 (95% CI 0.39-4.15) when nonmelanoma skin cancer was excluded. Short duration of follow-up and rarity of malignancies and serious infections are limitations. There is a small increased risk of overall infection with the short-term use of TNF antagonists for psoriasis that may be attributable to differences in follow-up time between treatment and placebo groups. There was no evidence of an increased risk of serious infection and a statistically significant increased risk in cancer was not observed with short-term use of TNF inhibitors.

The use of etanercept in a patient with disseminated tuberculosis

Tumor necrosis factor (TNF) is a central regulator of chronic inflammatory diseases and plays a major role in the host immune system against tuberculosis (TB). TNF antagonists, infliximab and etanercept are effective in treating chronic inflammatory diseases by inhibiting TNF, but increase the risk of TB as a result of immunosuppression. Previous studies have shown that the risk of TB is greater in patients who received infliximab than in those who received etanercept and several hypotheses on the action mechanisms of the two agents have been presented in order to explain this difference in the risk of TB. As the clinical use of TNF antagonists increase, the incidence rate of TB may increase. Therefore, it is necessary that clinicians considering the use of TNF antagonists pay much attention to the prevention and control of TB and understand the mechanisms of action of the TNF antagonists. This case shows that etanercept treatment can be safely administered during the treatment of TB. In the future, additional studies will be needed to determine the safety of etanercept and the optimal time for the administration of etanercept during the TB treatment.

TNF antagonists in the treatment of inflammatory bowel disease: Results of a survey of gastroenterologists in the French region of Lorraine

We conducted a survey of nonacademic gastroenterologists to evaluate the use of tumor necrosis factor (TNF) antagonists in inflammatory bowel disease (IBD). A total of 100 questionnaires were sent by mail to a representative sample of gastroenterologists practicing in the French region of Lorraine. Forty-six practitioners responded to the survey, of whom 95.5% prescribed scheduled infliximab treatment. After 6 months of infliximab in combination with azathioprine, 55% then prescribed infliximab as monotherapy. A complete pretherapeutic assessment was performed by only one fourth of the gastroenterologists. When the PPD skin test measured 7 mm, nearly half of the physicians introduced anti-TNF therapy without chemoprophylaxis (versus only 2.4% when the diameter was 11 mm). In the event of quiescent Crohn's disease (CD) after 1 year of anti-TNF treatment, 35.7% stopped the drug. In refractory CD, 72.7% prescribed infliximab as the first-line therapy (versus 27.3% who used adalimumab). In patients with urinary tract infection, 44.2% initiated antibiotics and delayed anti-TNF treatment, while 46.5% initiated anti-TNF therapy along with antibiotic therapy. This study is the first survey upon the use of TNF antagonists by nonacademic gastroenterologists, and the findings suggest that physicians using these drugs may require more information about the pretherapeutic assessment and management of the infectious risk.

Tumor Necrosis Factor Inhibition and Invasive Fungal Infections

Candida albicans and Aspergillus fumigatus occur ubiquitously in nature; C. albicans is part of the natural flora of most healthy individuals, and A. fumigatus is commonly found in soil, plant debris, and indoor air. Neither fungus poses a threat to healthy individuals, but each can cause fatal infections in immunocompromised patients. The use of tumor necrosis factor (TNF) antagonists for the treatment of rheumatoid arthritis and other autoimmune diseases has been associated with an increased incidence of opportunistic infections, including infections with both of these fungi. Because the use of TNF antagonists is expected to increase in the future, understanding the role that TNF plays and the effect of its antagonism on host defense against infections with these fungi is critical for reducing the associated morbidity and mortality.

Adalimumab for Rheumatoid Arthritis

Third-party payors and national health systems require evidence that new medications for rheumatoid arthritis are cost effective. To determine cost effectiveness, one must consider the cost of a given therapy versus the long-term cost of the disease, with and without therapy. The direct and indirect costs of rheumatoid arthritis over the course of the disease, including the considerable costs related to hospitalization and disability, have been quantified. Resource utilization and treatment costs are high for patients with rheumatoid arthritis, and there is a strong link between functional disability and direct cost of care. Traditional disease-modifying antirheumatic drugs (DMARDs) [such as methotrexate and gold] have limited long-term effects in improving lives and avoiding costs for patients with rheumatoid arthritis. Tumor necrosis factor (TNF) antagonists, the newest class of rheumatoid arthritis drug therapies, significantly improve patient outcomes, including reducing the signs and symptoms of rheumatoid arthritis, improving physical function and health-related quality of life, and inhibiting radiographie damage. Failing to treat rheumatoid arthritis effectively is very costly; effective treatment includes early, aggressive therapy. As a result, the National Health Service in the UK, other societal decision-makers, and third-party payors have recommended the use of TNF antagonists, in many instances, for the treatment of rheumatoid arthritis. The TNF antagonists — infliximab, etanercept, and the most recently approved, adalimumab — address the limitations of traditional DMARDs, thus setting a new therapeutic standard for rheumatoid arthritis. Data from three key studies (Anti-TNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis, DE019 and DE011) indicate that adalimumab provides a rapid, sustainable, predictable, and significantly greater reduction in the signs and symptoms of rheumatoid arthritis than traditional DMARDs. Adalimumab yields significantly less structural joint damage as measured by the total Sharp scores and scores on its two major components: joint erosions and joint space narrowing. It also improves physical function (as measured by the Health Assessment Questionnaire Disability Index) and health utility (as measured by the Health Utilities Index Mark 3). In conclusion, rheumatoid arthritis and other musculoskeletal diseases are costly, but an upfront investment in highly effective therapies may provide long-term cost savings compared with traditional therapies. The immediate, out-of-pocket costs of TNF antagonists are greater than traditional DMARDs, but with the potential to significantly improve response rates, inhibit structural joint damage, and improve disability and health utility, TNF antagonists have the potential to be more cost effective over the long run. TNF antagonists can be valuable for patients in need and therefore appropriate for reimbursement by national health systems and third-party payors.