TNF Inhibitors In Patients Research Articles

PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs

ObjectiveTo compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a...

Ex-vivo Cell-based Assay for Assessment of Response to TNF Inhibitors in Patients with Rheumatic Diseases.

TNF inhibitors (TNFi) comprise 5 products whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of the patients respond inadequately to TNFi. The different TNFi downstream signalling may lead to their clinical efficacy. Several reports showed that TNFi exhibited differential effects on Th17 cells. We analyzed the different TNFi effects on IL-17A expression in the peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases in order to evaluate the predictive capability of responses in an ex-vivo setting. PBMCs were co-cultured with the different TNFi or medium (control), and IL-17A mRNA levels were analyzed by qPCR. IL-17A expression levels in response to 4 TNFi (except certolizumab pegol) were compared with control. IL-17A expression in the assay was correlated to the clinical responses. Assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. The results of a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the different TNFi with 89.5% accuracy. The assay predicted the responses of a prospective cohort (n = 54) to specific TNFi with 79% accuracy. This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.

The safety and efficacy of TNF inhibitors in patients with Behçet's disease: Retrospective study from eastern Turkey

ObjectiveWe aimed to evaluate the clinical features, disease course, and associated factors for outcome in severe/refractory BD patients receiving TNF-i treatment. Material and methodsThis retrospective study was conducted by reviewing medical records from a tertiary referral center in Van province in Eastern Turkey. Data were obtained from patients' charts followed up between June 2019 and June 2022. ResultsWe included 469 BD patients (59.3% male) whose 80 patients (17%) received TNF-i treatment in the study. The mean ± standard deviation of the patient age was 36.7 ± 10.1 years and the median (IQR) disease duration was 12 (12) years. IFX and ADAwere initiated in 67.5% (n = 54) and 32.5% (n = 26) patients, respectively. Overall and first-line retention rates of TNF-i were 84.7% and 92.6% for IFX and 83.3% and 80.8% for ADA, respectively. IFX was discontinued in 9 patients which were in 2 patients due to allergic reaction and tuberculosis, 3 patients for inefficacy, one patient for heart failure, and one patient for orbital zona. Although no serious adverse event was observed with ADA, 5 patients switched to IFX due to inefficacy. Overall, 72 patients (90%) resumed TNF-i at the end of the study; TNF-i was discontinued in 3 patients (3.8%) due to severe adverse events and in 5 patients (6.2%) with prolonged remission. ConclusionIn our study, no case of death was observed in TNF-i receiving patients. Most patients achieved attack-free and CS-free disease and retained TNF-i treatment. TNF inhibitors appear to be safe and effective in patients with severe/refractory Behçet's disease.

Risk of extended major adverse cardiovascular event endpoints with tofacitinib versus TNF inhibitors in patients with rheumatoid arthritis: a post hoc analysis of a phase 3b/4 randomised safety study

ObjectivesCompare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors...

Association of HLA-DRB1 locus with treatment response to abatacept or TNF inhibitors in patients with seropositive rheumatoid arthritis

The strongest genetic risk factor for rheumatoid arthritis (RA) has been known as HLA-DRB1 based on amino acid positions 11, 71, and 74. This study analyzed the association between specific HLA-DRB1 locus and treatment response to abatacept or TNF inhibitors (TNFi) in patients with seropositive RA. A total of 374 Korean RA patients were treated with abatacept (n = 110) or TNFi (n = 264). Associations between HLA-DRB1 and treatment response after 6 months were analyzed using multivariable logistic regression. Seropositive RA patients with HLA-DRB1 shared epitope (SE) had a favorable response to abatacept (OR = 3.67, P = 0.067) and an inversely associated response to TNFi (OR 0.57, P = 0.058) based on EULAR response criteria, but the difference was not statistically significant in comparison to those without SE. In analyses using amino acid positions of HLA-DRB1, a significant association was found between valine at amino acid position 11 of SE and good response to abatacept (OR = 6.46, P = 5.4 × 10–3). The VRA haplotype also showed a good response to abatacept (OR = 4.56, P = 0.013), but not to TNFi. Our results suggest that treatment response to abatacept or TNFi may differ depending on HLA-DRB1 locus in seropositive RA, providing valuable insights for selecting optimal therapy.

Occurrence and prediction of flare after tapering of TNF inhibitors in patients with axial spondyloarthritis.

Patients with axial spondyloarthritis (axSpA) in clinical remission tapered Tumor Necrosis Factor inhibitor (TNFi) therapy according to a clinical guideline. During 2-years' follow-up, we aimed to investigate flare frequency, dose at which flare occurred, type of flare and predictors thereof. Patients in clinical remission (Bath ankylosing spondylitis disease activity index (BASDAI)<40, physician global score<40 and without disease activity the previous year) tapered TNFi to 2/3 standard dose at baseline, 1/2 at week (w) 16, 1/3 at w32 and discontinuationed at w48. Flare was defined as: BASDAI flare (BASDAI≥40 and Δ≥20) and/or clinical flare (development of inflammatory back pain, musculoskeletal or extra-articular manifestations and/or ASDAS-CRP increase ≥0.9) and/or MRI flare (≥2 new/worsened inflammatory lesions). Of 108 patients, 106 (99%) flared before 2 years: 29 patients (27%) at 2/3 standard dose, 21 (20%) at 1/2 dose, 29 (27%) at 1/3 dose and 27 (25%) after discontinuation. One-hundred-and-five (99%) had clinical flare, 25 (24%) BASDAI flare and 23 (29% of patients with MRI) MRI flare. Forty-one patients (41%) fulfilled the ASAS-definition of clinically important worsening (≥0.9 increase since baseline). Higher baseline physician global score was an independent predictor of flare after tapering to 2/3 (Odds ratio=1.19 (95% Confidence Interval=1.05-1.41);p=0.011). Changes in clinical and/or imaging variables in the 16 weeks prior to tapering did not predict flare. Almost all (99%) axSpA patients in clinical remission flared during tapering to discontinuation, but above half not before receiving 1/3 dose or less. Higher physician global score was an independent predictor of flare.

The Influence of TNFRSF1B, PADI4, and miRNA 499 Gene Polymorphisms on Susceptibility and Responsiveness to TNF Inhibitors in Patients with Rheumatoid Arthritis

The Influence of TNFRSF1B, PADI4, and miRNA 499 Gene Polymorphisms on Susceptibility and Responsiveness to TNF Inhibitors in Patients with Rheumatoid Arthritis

Efficacy of biologic and small molecule agents as second-line therapy after exposure to TNF inhibitors in patients with ulcerative colitis: A propensity-matched cohort study.

There is limited real-world data on comparative effectiveness of different biologic or small molecule agents as second-line therapies in patients with ulcerative colitis (UC) with prior exposure to a tumour necrosis factor inhibitor (TNFi). We conducted a retrospective cohort study using TriNetX, a multi-institutional database to assess the efficacy of tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis (UC) with prior exposure to a TNFi. Failure of medical therapy was defined as a composite outcome of intravenous steroids or colectomy within 2 years. One-to-one propensity score matching was performed for demographics, disease extent, mean haemoglobin, C-reactive protein, albumin and calprotectin, prior IBD medications and steroid use between cohorts. Among 2141 patients with UC and prior exposure to TNFi, 348 (16.2%), 716 (33.4%) and 1077 (50.3%) were switched to tofacitinib, ustekinumab and vedolizumab, respectively. After propensity-score matching, there was no difference in the composite outcome (aOR: 0.77, 95% CI: 0.55-1.07) but higher risk of colectomy (aOR: 2.69, 95% CI: 1.31-5.50) in the tofacitinib cohort than the vedolizumab cohort. There was no difference in the risk of composite outcome (aOR: 1.29, 95% CI: 0.89-1.86) but higher risk of colectomy (aOR: 2.63, 95% CI: 1.24-5.58) in the tofacitinib cohort than the ustekinumab cohort. The vedolizumab cohort had a higher risk of composite outcome (aOR: 1.67, 95% CI: 1.29-2.16) than the ustekinumab cohort. Ustekinumab might be the preferred second-line therapy over tofacitinib and vedolizumab in patients with UC that were previously exposed to a TNFi.

Discontinuation of tofacitinib and TNF inhibitors in patients with rheumatoid arthritis: analysis of pooled data from two registries in Canada

ObjectivesThe similarity in retention of tumour necrosis factor inhibitors (TNFi) and tofacitinib (TOFA) was previously reported separately by the Ontario Best Practices Research Initiative and the Quebec cohort Rhumadata. However,...

Paradoxical cutaneous manifestations induced by TNF inhibitors in patients with inflammatory bowel disease

Background: Anti-TNF drugs have revolutionized the management of numerous inflammatory diseases, yet they may produce paradoxical effects. Materials and Methods: A descriptive study was conducted on patients with chronic inflammatory bowel disease (IBD) on anti-TNF therapy who had developed paradoxical psoriasis. Results: Out of a total of 218 patients followed for IBD on TNF inhibitors, five presented with paradoxical psoriasis. In four patients, a specific treatment for psoriasis was associated with anti-TNF treatment. In one patient, a swap to ustekinumab was decided. Good progress was noted in four patients. In one, there was no improvement of the psoriasis on methotrexate, which was switched to another anti-TNF agent. Conclusion: In our experience, TNF inhibitor-induced psoriasis is relatively rare (prevalence of 2.3%). The choice of treatment is reached by assessing the benefit-risk balance. Key words: Paradoxical cutaneous manifestations; TNF inhibitors; Cutaneous manifestations; Inflammatory bowel disease

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study

ObjectivesTo evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years.MethodsPsABio (NCT02627768), a prospective, observational study, followed...

The use of drug monitoring of infliximab and adalimumab to optimize the treatment of inflammatory bowel diseases in children

Introduction. The effectiveness of the use of TNF inhibitors in patients with inflammatory bowel diseases (IBD) has been shown. 20-40% of patients are known to fail to respond to received therapy, and 10-30% of patients experience a loss of effect by the year of therapy. Objective is to evaluate the information content of therapeutic drug monitoring (TDM) for effective treatment with TNF blockers (infliximab - IFX, adalimumab - ADA) in IBD children. Materials and methods. There were examined seventy four children on IFX therapy including 66 children on ADA therapy. The age of the children ranged from 3.4 to 18 years. Residual levels of IHF and ADA were determined using a lateral flow immunoassay. Statistical data processing was performed using the Statistica 10.0, SPSS 16 software. Differences between groups were assessed using the nonparametric Mann-Whitney U test. Results. IFX levels (less than 3 µg/ml) were detected in 64% of cases, ADA (less than 5 µg/ml) in 21% of cases. The residual level of IFX and ADA in remission significantly exceeded the level of drugs in groups of children in exacerbation. An inverse relationship was observed between the residual level of IFX (r = -0.68, p = 0.000) and ADA (r = -0.31, p = 0.000) and the number of days after drug administration. Anti-IFX antibodies were found in 27.3% in the exacerbation group and in 5.8% in remission (p &lt; 0.001). Antibodies to ADA in children with IBD were found in 4 patients with a low concentration of the drug (2.57 ± 0.45 µg/ml) in the serum in a state of exacerbation. In patients on anti-TNF therapy, empirical dose selection revealed a residual level lower than in children in whom dose adjustment was carried out taking into account the residual concentration of drugs. Conclusion. The use of TDM TNF blockers in combination with the determination of antibodies to drugs can significantly increase the effectiveness of therapy in IBD children.

Psoriasis, inflammatory bowel disease, and uveitis as paradoxical adverse effects induced by TNF inhibitors in patients with immune-inflammatory rheumatic conditions

Despite their known benefits, tumor necrosis factor alpha inhibitors (TNFi) may cause certain unexpected side effects, such as the aggravation of pre-existing autoimmune conditions or inducing the onset of new inflammatory conditions, these reactions being called “paradoxical adverse effects’’ (PAEs). The spectrum of TNFi-induced PAEs is vast and may include dermatological disease (frequently - psoriasiform skin reactions), gastroenterological disease (inflammatory bowel disease), ophthalmological disease (uveitis) and other autoimmune conditions (lupus-like reactions, vasculitis). PAEs are characterized by complex physio-pathological mechanisms which remain a matter of further research and may significantly impact the patients’ evolution and quality of life. Importantly, a large number of patients require the cessation of TNFi treatment, as well as other types of therapeutic interventions. The present review aimed to analyze recent findings regarding certain paradoxical adverse effects (psoriasis, inflammatory bowel disease, and uveitis) in patients with RA, ankylosing spondylitis (AS), and PsA treated with TNFi.

Treatment of axial spondyloarthritis: an update.

Diagnosis and management of axial spondyloarthritis (axSpA) has vastly improved over the past two decades. With advances in the discernment of immunopathogenesis of this disease, new therapies have become available, which are associated with substantial improvement in symptoms, signs and quality of life. The four broad categories of approved treatment options are physical therapy and exercise (which have been known to be beneficial for millennia), NSAIDs (since the 1950s), TNF inhibitors (first FDA approval in 2003) and IL-17 inhibitors (first FDA approval in 2016). In addition, there have been a host of new developments in the axSpA field, including new treatment guidelines, the FDA approval of three biologic DMARDs to treat non-radiographic axSpA, the FDA and EMA approval of Janus kinase (JAK) inhibitors for ankylosing spondylitis, new data on the effect of biologic DMARDs on structural progression in ankylosing spondylitis, strategy trials on tapering or stopping TNF inhibitors in patients in remission, trials of treat-to-target strategy in axSpA, and several new molecules in phase III studies. This Review explores the developments in the management of axSpA.

The Comparative Risk of Serious Adverse Events With Tofacitinib and TNF Inhibitors in Patients With Ulcerative Colitis: The Korean Experience as Revealed by a National Database.

Tofacitinib is an oral, small-molecule Janus kinase inhibitor approved in South Korea for the treatment of moderate to severe ulcerative colitis (UC) on May 1, 2019. However, safety data are lacking. We investigated the incidence of serious adverse events (SAEs) in patients with UC using tofacitinib from the National Health Insurance Service database. In all, 1,026 UC patients were enrolled in this study. The overall incidences (100 person-years; 95% confidence interval) of SAEs were 4.06 (1.63–8.36) and 6.30 (4.59–8.43) in the tofacitinib and anti-TNFi groups, respectively. No thromboembolic event occurred and major cardiovascular events occurred in only three patients (two unstable angina and one congestive heart failure) in the tofacitinib group. The incidence of herpes zoster and tuberculosis did not differ between the two groups. There was no difference in the overall incidence of SAEs, including thromboembolic events, between tofacitinib- and TNFi-treated UC patients.

Comparison of the efficacy and risk of discontinuation between non-TNF-targeted treatment and a second TNF inhibitor in patients with rheumatoid arthritis after first TNF inhibitor failure.

Objectives:Despite improved care for rheumatoid arthritis (RA) patients, many still experience treatment failure with biologic disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs [tsDMARDs; typically Janus kinase inhibitors (JAKi)], and eventually switch to other agents. We compared the efficacy of a second tumor necrosis factor inhibitor (TNFi) and non-TNF-targeted treatment as the second-line treatment in patients showing an insufficient response to the first TNFi.Methods:Patients were included if they had received at least one prescription for a TNFi, and at least one follow-up prescription for a second TNFi or non-TNF-targeted treatment after discontinuation of the first drug. In total, 209 patients were analyzed, including 69 with a second TNFi and 140 with a non-TNF-targeted treatment (106 non-TNFi biologics and 34 JAKi). Cox regression was used to estimate the hazard ratio (HR) for discontinuation.Results:The mean follow-up period after switching was 28.0 (range: 0–80) months and 24.4% of the 209 patients switched or discontinued the second drug. In multivariate Cox proportional hazard analysis, the non-TNF-targeted treatment group had a lower likelihood of discontinuing their treatment than the second TNFi group [HR = 0.326, 95% confidence interval (CI): 0.170–0.626, p = 0.001]. When analyzed separately, the risk of discontinuation was significantly lower in both the non-TNFi biologic (HR = 0.318, 95% CI: 0.160–0.633, p = 0.001) and JAKi (HR = 0.356, 95% CI: 0.129–0.980, p = 0.046) groups than in the second TNFi group.Conclusion:Our study supported switching to a non-TNF-targeted treatment instead of TNF cycling in patients with RA showing an inadequate response to initial TNFi.

Posttraumatic Stress Disorder, Depression, Anxiety, and Persistence of Methotrexate and TNF Inhibitors in Patients with Rheumatoid Arthritis.

ObjectiveTo examine the relationship of posttraumatic stress disorder (PTSD) with earlier treatment discontinuation and medication adherence in US veterans with rheumatoid arthritis (RA).MethodsVeterans Affairs (VA) administrative data (2005‐2014) were used to define unique dispensing episodes of methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) for veterans with RA. Diagnosis codes were used to categorize patients into mutually exclusive groups: PTSD (with/without depression/anxiety), depression/anxiety without PTSD, and neither psychiatric diagnosis. Multivariable Cox proportional hazards models were used to evaluate associations between psychiatric diagnoses and time to disease‐modifying antirheumatic drug discontinuation (lapse in refill >90 days). Multivariable logistic regression was used to examine associations of diagnoses with medication nonadherence (proportion of days covered <0.8).ResultsThere were 15 081 dispensing episodes of MTX and 8412 dispensing episodes of TNFi. PTSD was independently associated with a greater likelihood of earlier discontinuation of both MTX (hazard ratio [HR] 1.15 [1.10‐1.21]) and TNFi (HR 1.20 [1.13‐1.28]). Depression/anxiety had a comparable risk of discontinuation for both MTX (HR 1.14 [1.10‐1.19]) and TNFi (HR 1.16 [1.10‐1.22]). Depression/anxiety, but not PTSD, was associated with higher odds of MTX (odds ratio [OR] 1.12 [1.03‐1.22]) and TNFi (OR 1.14 [1.02‐1.27]) nonadherence.ConclusionVeterans with RA and comorbid PTSD, depression, or anxiety had poor persistence of MTX and TNFi therapies. These results suggest that earlier discontinuation and low adherence to therapy among patients with RA with these psychiatric comorbidities may contribute to worse disease outcomes. Mechanisms by which these comorbidities contribute to lower adherence deserve further investigation and may lead to targeted interventions to improve disease outcomes.

Effectiveness of switching between TNF inhibitors in patients with axial spondyloarthritis: is the reason to switch relevant?

BackgroundTo investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA).MethodsPatients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models.ResultsIn total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure.ConclusionPatients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.

Effectiveness of secukinumab versus an alternative TNF inhibitor in patients with axial spondyloarthritis previously exposed to TNF inhibitors in the Swiss Clinical Quality Management cohort

ObjectiveTo compare effectiveness of treatment with secukinumab (SEC) with that of alternative tumour necrosis factor inhibitors (TNFis) in patients with axial spondyloarthritis (axSpA) after withdrawal from one or more TNFis.MethodsPatients...