Tumor Necrosis Factor-alpha Inhibitor Therapy Research Articles

The safety and efficacy of tumor necrosis factor-alpha inhibitor on pregnancy outcomes in patients with unexplained recurrent miscarriage

ObjectivesAlthough tumor necrosis factor-alpha inhibitor (TNFi) treatment may improve pregnancy outcomes in unexplained recurrent miscarriage (URM) patients, evidence for its efficacy and safety is still insufficient. The goal of this study was to evaluate the efficacy and safety of TNFi on pregnancy outcomes in patients with URM. MethodsThis retrospective study was conducted at a single institution in China, involving 121 patients treated with TNFi for URM from 2019 to 2022. Patients enrolled were divided into treatment group (receiving TNFi and heparin therapy) and control group (receiving heparin therapy). The outcome variables were the 24-week live birth rate, miscarriage rate, ectopic pregnancy rate, neonatal outcomes, and adverse events. ResultsIn our study, patients receiving TNFi treatment exhibited a significant increase in live birth rates, achieving 71.2 % compared to the 50.9 % observed in the control group (OR 2.507, 95 % CI: 1.127–5.579). Concurrently, there was a discernible reduction in the miscarriage rate within the TNFi-treated group, marking 24.2 %, in contrast to 43.6 % in the control group (OR 0.387, 95 % CI: 0.170–0.884). Subgroup analyses further illuminated that those under the age of 35 benefitted remarkably from TNFi treatment, with live birth rates soaring to 62.5 % (OR 2.525, 95 % CI: 1.041–6.125). For patients with a history of two miscarriages, the TNFi regimen significantly augmented the live birth rate to 58.9 % (OR 3.044, 95 % CI: 1.039–8.921). Patients with a normal weight range registered a 58.4 % live birth rate post-TNFi treatment (OR 4.261, 95 % CI: 1.539–11.397). Notably, an evident interaction between BMI and TNFi treatment was identified, suggesting a potential modulatory role of BMI on the therapeutic efficacy of TNFi. About safety assessments, neither the TNFi-treated group nor the control manifested any significant disparities in liver function abnormalities, platelet count anomalies, or other pregnancy-related complications. ConclusionsTNFi, alongside basic therapy, notably enhances the live birth rate in URM patients under 35, with two prior miscarriages or a normal BMI, without increasing adverse event risk. Further prospective studies are essential to validate these observations.

Secukinumab after first-line tumor necrosis factor-alpha inhibitor therapy in psoriatic arthritis: A real-world retrospective cohort study.

This study compared the secukinumab treatment responses and adverse effects in psoriatic arthritis patients who received secukinumab as second-line with those that received secukinumab after two or more tumor necrosis factor-alpha (TNF-α) inhibitors. The retrospective study included 68 psoriatic arthritis patients followed up between October 2018 and October 2021. The patients were divided into two groups according to their anti-TNF-α treatment history. Group 1 consisted of 29 patients (11 males, 18 females; mean age: 45.3±13.3 years; range, 21 to 69 years) who had previously received one anti-TNF-α agent, while Group 2 included 39 patients (18 males, 21 females; mean age: 46.4±13.0 years; range, 24 to 70 years) who had been treated with two or more anti-TNF-α agents. Treatment responses of the groups were measured and compared using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Visual Analog Scale (VAS). A posttreatment BASDAI score ≤4 was used as a criterion for remission. The mean duration of secukinumab treatment was 16.6±12.7 months for Group 1 and 16.0±11.6 months for Group 2 (p=0.84). Both groups responded significantly to secukinumab in terms of BASDAI and VAS scores (p<0.001 and p<0.001, respectively). Group 1 had a greater decline in BASDAI and VAS scores than Group 2 (p=0.045 and p=0.032, respectively). Furthermore, the remission rate was greater in Group 1 compared to Group 2 (58% vs. 34%, p=0.03). The adverse effects of secukinumab treatment were an allergic reaction in Group 1 and one case of ulcerative colitis in Group 2. Second-line secukinumab treatment resulted in a greater decline in BASDAI and VAS scores. Moreover, secukinumab achieved a significantly higher rate of remission when it was used as second-line therapy after one anti-TNF-α agent.

Effect of tumor necrosis factor inhibitors on interstitial lung disease in rheumatoid arthritis: angel or demon?

Objectives: This study evaluated the correlation between tumor necrosis factor alpha inhibitor (TNF-I) and interstitial lung disease (ILD) in rheumatoid arthritis (RA). We aimed to raise awareness and consummate therapy by summarizing the characteristics of the adverse events of ILD.Methods: A comprehensive search of the PubMed, Embase, Ovid, Cochrane, China National Knowledge Infrastructure, and Wanfang databases was performed from inception to November 2018. Statistical analysis of demographic characteristics, clinical features, and relative risks was performed using Microsoft Excel 2007 and SPSS version 20.0.Results: A total of 7 eligible articles and another 28 case reports were enrolled. The 7 cohort studies demonstrated the tendency that ILD cases might not benefit from TNF-I therapy. TNF-I might be associated with ILD adverse events. The case reports further confirmed these findings, as most (87.5%) of the cases showed that TNF-1 was harmful to patients with ILD and even resulted in a 35% mortality rate. Further investigation revealed that ILD adverse events tended to appear in female patients with a long RA history (p<0.05). The subgroup analysis suggested that early detection and precise treatment are key factors in determining survival or death when an ILD adverse event occurs. A large proportion of ILD adverse events (48.6%) appeared at 2.38±1.03 weeks after the infusion of infliximab.Conclusion: A fresh look at the evidence highlights that TNF-I might be associated with ILD adverse events in RA, which can induce more severe pulmonary symptoms and even result in death. Therefore, more attention should be paid to effective prevention, early diagnosis, and precise management. Notably, further prospective cohort studies are warranted to better interpret the association or causality between TNF-I and ILD.

Predictive clinical-genetic model of long-term non-response to tumor necrosis factor-alpha inhibitor therapy in spondyloarthritis.

Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society(ASAS) criteria. From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. The clinical factors that significantly increased the non-response rate were: global visual analog scale(VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy.

Economic Burden of Switching to a Non-Tumor Necrosis Factor Inhibitor Versus a Tumor Necrosis Factor Inhibitor Biologic Therapy among Patients with Rheumatoid Arthritis.

The objective of this study was to examine healthcare resource utilization (HRU) and costs associated with switching to another tumor necrosis factor alpha inhibitor (TNFi) therapy versus a non-TNFi therapy among patients with rheumatoid arthritis (RA) discontinuing use of an initial TNFi biologic therapy. Patients with ≥2 RA diagnoses who used ≥1 TNFi on or after their initial RA diagnosis were identified in a US employer-based insurance claims database. Patients were selected based on ≥1 claim of another TNFi or a non-TNFi biologic therapy (occurring after 2010, and within 30days before to 60days after discontinuation of the initial TNFi), and continuous insurance ≥6months before (baseline period) and ≥12months after the switch date (study period). Patient demographic and clinical characteristics were measured during the baseline period. All-cause and RA-related HRU and costs were analyzed during the 12-month study period using multivariable regression analysis controlling for baseline characteristics and selected comorbidities. Of the 1577 patients with RA that switched therapies, 1169 patients used another TNFi and 408 patients used a non-TNFi biologic. The most commonly used initial TNFi treatments were etanercept (50%) and adalimumab (34%) among the TNFi cohort, and infliximab (39%) and etanercept (28%) among the non-TNFi cohort. The TNFi cohort had significantly fewer outpatient visits [all-cause: 23.01 vs. 29.77visits/patient/year; adjusted incidence rate ratio (IRR)=0.78, P<0.001; RA-related: 7.42 vs. 13.58; adjusted IRR=0.58, P<0.001] and rheumatologist visits (all-cause: 4.01 vs. 6.81; adjusted IRR=0.66, P<0.001; RA-related: 3.23 vs. 6.40; adjusted IRR=0.58, P<0.001) than the non-TNFi cohort. All-cause total costs were significantly lower for patients who switched to another TNFi instead of a non-TNFi therapy ($36,932 vs. $44,566; adjusted difference=$7045, P<0.01), as were total RA-related costs ($26,973 vs. $31,735; adjusted difference=$4904, P<0.01). Adult patients with RA discontinuing TNFi therapy who switched to an alternative TNFi incurred lower healthcare costs than patients who switched to a non-TNFi biologic. AbbVie, Inc.

Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis.

The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score.

Efficacy of tumor necrosis factor-alpha inhibitors in fistulising perianal Crohn’s disease

Tumor necrosis factor-alpha inhibitors are increasingly used in the treatment of severe Crohn's disease. The aim of the authors was to assess retrospectively the short and long term efficacy of tumor necrosis factor-alpha inhibitors in fistulising Crohn's disease. Responses to therapy was determined using Crohn's Disease Activity Index, Perianal Disease Activity Index, the rate of complete fistula closure and the additional surgical procedures during biological therapy. After 12 weeks the perianal activity was decreased in more than 80% of the cases, and the complete remission rate was about 60%. After one year of therapy about one third of the patients had fistula closure, but after cessation of the biological therapy recurrence of fistulas was detected in every second patient. In most cases additional immunosuppressive therapy was necessary during biological treatment. During the one-year therapy period additional surgical treatments were performed in 45% of patients; seton insertion and abscess drainage were the most frequent procedures. Tumor necrosis factor-alpha inhibitor therapy is effective in the treatment of perianal Crohn's disease, however, additional immunosuppressive drugs and rectum sparing surgical procedures were necessary during the one-year treatment period. Because of the high rate of fistula recurrence, long term tumor necrosis factor-alpha treatment may be useful.

New-Onset Inflammatory Bowel Disease During Tumor Necrosis Factor-Alpha Inhibitor Therapy for Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis: A Review of the Food and Drug Administration Adverse Event Reporting System and Literature

Purpose: New-onset inflammatory bowel disease (IBD) has been reported as a paradoxical adverse event (PAE) in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors. We conducted a review of the Food and Drug Administration Adverse Event Reporting System (AERS) and published literature for cases of IBD reported in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) with TNF-α inhibitor therapy. Methods: The FDA AERS is a publicly available database of voluntary reports for post marketing surveillance of all approved drugs. 2,562,390 files from 2003 - June 2011 were downloaded and analyzed using SSPS 20 (IBM Co. Armonk, NY). Files were queried for reaction terms from the Dictionary for Regulatory Activities - inflammatory bowel disease, Crohn's disease (CD), ulcerative colitis (UC), and ulcerative proctitis reported with infliximab, etanercept, adalimumab, golimumab, and certolizumab and their trade names. “Primary suspect” reports were selected where indication for use was RA or JRA, (diseases are not associated with increased risk of IBD). A MEDLINE search was performed for published English language literature using MESH terms “inflammatory bowel disease/chemically induce”, “Crohn's disease/chemically induced”, and “ulcerative colitis/chemically induced” combined with the Boolean operator “OR” between terms. Additional articles were found in bibliographies of selected articles. Results: There were 183 cases of IBD after TNF-α inhibitor therapy (Table 1). The majority (95; 51.91%) were cases of CD, 61 (33.33%) were UC, and 27 (14.75%) were unspecified IBD. IBD was most commonly (105 cases; 57.37%) reported after etanercept and during therapy for RA. 77.4% of cases were females. The MEDLINE search revealed 30 previously described cases, 2 in RA patients (1 on infliximab and 1 on adalimumab) and 28 in JRA patients (26 on etanercept, 2 on infliximab). 26 JRA cases were histologically verified; 18 cases were CD, 3 were UC, and 5 were indeterminate IBD.Table 1: Inflammatory bowel disease with TNF-α inhibitor therapy reported to FDA AERSConclusion: TNF-α inhibitor therapy may be associated with new-onset of IBD and appears to occur most commonly in RA patients.

Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: A review and recommendations for management

Tumor necrosis factor inhibitory agents are currently considered to be contraindicated in psoriatic patients with hepatitis B. We aim to provide guidance to dermatologists on the use of tumor necrosis factor inhibitor therapy in these patients. The current literature was reviewed regarding the use of tumor necrosis factor-alpha inhibitory agents (etanercept, adalimumab, and infliximab) in psoriatic patients with particular reference to hepatitis B infection. Tumor necrosis factor-alpha inhibitor therapy may result in reactivated hepatitis B in hepatitis B surface antigen-positive patients with psoriasis. This also occurs, although less frequently in patients with an isolated positive hepatitis B core antibody. Thus, all psoriasis patients should be screened for hepatitis B surface antigen plus hepatitis B core antibody prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Infliximab has been associated with more reactivation cases than the other 2 agents and fatalities have been reported with this agent. Evidence is presented that the risk of reactivation can be greatly minimized or eliminated by early or pre-emptive antiviral therapy. The data is largely based on small case series that are retrospective in nature. Hepatitis B screening is essential prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Psoriatic patients found to be hepatitis B surface antigen or hepatitis B core antibody-positive should be referred to an appropriate specialist for evaluation and therapy. This would allow for the safe use of tumor necrosis factor-alpha inhibitors in psoriatic patients despite recently published guidelines to the contrary.

Palisaded neutrophilic and granulomatous dermatitis presenting in a patient with rheumatoid arthritis on adalimumab

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis that can present with many unique cutaneous manifestations including palisaded neutrophilic and granulomatous dermatitis (PNGD). The authors present a case of PNGD in a RA patient on adalimumab therapy. The potential association of PNGD and adalimumab therapy is discussed as well as a review of the literature of granulomatous eruptions involving patients with RA who are receiving tumor necrosis factor-alpha inhibitor therapy.

QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory prior to the initiation of tumour necrosis factor-alpha inhibitor therapy. However, no agreement exists on the best strategy for detecting LTBI in this population. The aim of the present study was to analyse the performance of the tuberculin skin test (TST) and QuantiFERON-TB Gold in-tube (QFT-GIT) on LTBI detection in subjects with immunomediated inflammatory diseases (IMID). The TST and QFT-GIT were prospectively performed in 398 consecutive IMID subjects, 310 (78%) on immunosuppressive therapy and only 16 (4%) had been bacillus Calmette-Guérin (BCG) vaccinated. Indeterminate results to QFT-GIT were found in five (1.2%) subjects. Overall, 74 (19%) out of 393 subjects were TST-positive and 52 (13%) were QFT-GIT-positive. Concordance between TST and QFT-GIT results was good (87.7%): 13 were QFT-GIT-positive/TST-negative and 35 QFT-GIT-negative/TST-positive. By multivariate analysis both tests were significantly associated with older age. Only the TST was associated with BCG vaccination and radiological lesions of past TB. Use of immunosuppressive drugs differently modulated QFT-GIT or TST scoring. Use of the QuantiFERON-TB Gold in-tube, as a screening tool for latent tuberculosis among immunomediated inflammatory disease subjects, is feasible. Until further data will elucidate discordant tuberculin skin test/QuantiFERON-TB Gold in-tube results, a strategy of simultaneous tuberculin skin and QuantiFERON-TB Gold in-tube testing in a low prevalence bacillus Calmette-Guérin vaccinated population, should maximise potentials of latent tuberculosis diagnosis.

Tumor necrosis factor inhibitors and infection complications

Rheumatoid arthritis patients are at heightened risk for infections because of intrinsic disease severity with associated inflammation, comorbid illnesses, and use of glucocorticoids and various immunosuppressives. Although several studies have reported up to a twofold increase in risk of serious infections in RA patients treated with anti-tumor necrosis factor-alpha agents, results from other studies have been conflicting. Comparing results from different studies is challenging because of differences in patient populations, heterogeneous prevalence of comorbidities, and differing patterns of concomitant medication use. Based on available evidence, an excess risk for infection occurs early after initiation of tumor necrosis factor-alpha inhibitor therapy. Additionally, special circumstances such as surgical procedures may increase infection risk. The appropriate use of biologics in the perioperative setting remains empiric at best.