TNF Inhibitors Research Articles

Methotrexate, Tofacitinib, and Biologic Disease-Modifying Antirheumatic Drug Safety and Effectiveness Among Patients with Rheumatoid Arthritis in Japan: CorEvitas Registry Observational Study.

The evolution of disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) has improved patient prognosis. However, more real-world safety/effectiveness data comparing methotrexate (MTX), tofacitinib, tumor necrosis factor inhibitors (TNFi), and non-TNFi biologic DMARDs (bDMARDs)are warranted. The CorEvitas RA Japan registry was used to identify patients with rheumatologist-diagnosed RA who initiated MTX/tofacitinib/TNFi/non-TNFi bDMARDs. Safety outcomes included incidence of major adverse cardiovascular events (MACE), total cardiovascular disease, total serious infections, total herpes zoster, and total malignancies (excluding non-melanoma skin cancer). Effectiveness outcomes included change from baseline (Δ) in Clinical Disease Activity Index (CDAI) and proportion of patients achieving a minimum clinically important difference (MCID) in CDAI at month6. Adjusted regression models were fit; marginal means were estimated. Overall, 1972 patients were included in the safety cohort: MTX (N = 298); tofacitinib (N = 253); TNFi (N = 663); non-TNFi (N = 758). Mean follow-up time was 3.8, 2.9, 3.0, and 2.9years for MTX, tofacitinib, TNFi, and non-TNFi, respectively. Adjusted incidence rates (IRs, patients with events/100 patient-years [95% confidence intervals]) for MACE and total cardiovascular disease, respectively, were numerically lower for MTX (0.34 [0, 0.83]; 0.42 [0, 0.92]) and TNFi (0.09 [0, 0.27]; 0.61 [0.15, 1.07]) versus tofacitinib (0.48 [0, 1.20]; 2.30 [0.38, 4.22]) and non-TNFi (0.77 [0.35, 1.19]; 1.28 [0.73, 1.82]). Serious infections were numerically higher for non-TNFi (4.47 [3.38, 5.56]); herpes zoster was higher for tofacitinib (7.41 [4.52, 10.29]), versus other groups. IRs for malignancies were comparable between groups. Mean ΔCDAI and rates of achieving MCID in CDAI at month6 were generally greater with tofacitinib versus other groups. Some variations in incidence of safety outcomes were observed between treatments, while certain effectiveness outcomes favored tofacitinib. Sample size variation between groups and low number of safety events limited the analysis. Further studies are warranted to investigate observed differences. GOV: NCT05572567.

Geographical Differences in the Safety and Efficacy of Tofacitinib Versus TNFi: APost Hoc Analysis of ORAL Surveillance.

In ORAL Surveillance, incidence rates (IRs) of major adverse cardiovascular events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) in cardiovascular (CV)-risk-enriched patients with rheumatoid arthritis (RA) were numerically greater with tofacitinib in North America versus the rest of the world, due to underlying risk factors. Here, we evaluated the safety and efficacy of tofacitinib versus tumor necrosis factor inhibitors (TNFi) among patients with RA across geographical regions. Patients with RA in ORAL Surveillance (NCT02092467), who were aged ≥ 50years with ≥ 1additional CV risk factor, received tofacitinib 5 or 10mg twice daily or TNFi; 45.9% were from either Poland or North America. This post hoc analysis stratified patients by region (Poland, North America, Other countries). Efficacy endpoints included Clinical Disease Activity Index, Disease Activity Score in 28 joints, with C-reactive protein (DAS28-4[CRP]), and Health Assessment Questionnaire-Disability Index (HAQ-DI). IRs and hazard ratios for adverse events were reported. Of 4362 patients (Poland, N = 759; North America, N = 1243; Other countries, N = 2360), more patients from North America versus Poland/Other countries had CV risk factors such as body mass index ≥ 30kg/m2 and history of diabetes/hypertension; however, more patients from Poland versus other regions were ever smokers and more patients from Poland/North America versus Other countries had history of coronary artery disease. MACE IRs were similar in North America and Poland, and numerically higher versus Other countries. IRs for malignancies (excluding NMSC) were numerically higher in NorthAmerica versus Poland/Other countries with tofacitinib. Serious infections IRs werenumerically higher in North America versus Poland across treatments. Venousthromboembolism/all-cause mortality IRs were generally comparable across regions. DAS28-4(CRP)/HAQ-DI improvements were generally lowest in North America. Differences in safety outcomes were driven by the presence of baseline risk factors; North America and Poland demonstrated a higher proportion of patients with some baseline CV risk factors/comorbidities versus Other countries. NCT02092467 (ClinicalTrials.gov).

Efficacy and Safety of Biologics in Polymyalgia Rheumatica: A Retrospective Study.

The study aimed to determine the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in the treatment of polymyalgia rheumatica (PMR) complicated by rheumatoid arthritis (RA). Patients with PMR which could be classified as RA and who were treated with bDMARDs were included in the analysis. The primary endpoint was the clinical Polymyalgia Rheumatica Activity Score (Clin-PMR-AS) after 26weeks of treatment, and the secondary endpoint was adverse events during the observation period. A total of 203 patients with PMR which was resistant or intolerant to glucocorticoids and could be classified as RA were receiving bDMARDs and were enrolled in the study. There were 83, 82, and 38 patients in the tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), and cytotoxic Tlymphocyte-associated antigen-4-immunoglobulin(CTLA4-Ig) groups, respectively. Twenty-six weeks after bDMARD initiation, Clin-PMR-AS levels were significantly lower in the IL-6Ri group as compared to other groups. Multiple regression analysis was performed with Clin-PMR-AS as the objective variable. Body mass index (BMI), history of bDMARDs, and IL-6Ri use were identified as factors involved in Clin-PMR-AS. After adjustment for group characteristics using inverse probability of treatment weighting with propensity scores, the Clin-PMR-AS score at 26weeks was significantly lower in the IL-6Ri group (9.0) than in both the TNFi (12.4, p = 0.004) and CTLA4-Ig (15.9, p = 0.003) group. IL-6Ri may potentially improve the disease activity of PMR compared to other bDMARDs.

Biologic and targeted synthetic disease-modifying anti-rheumatic drugs improve body composition in rheumatoid arthritis patients more than conventional synthetic disease-modifying anti-rheumatic drugs: Results from the PRESENT study.

The effects of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on body composition and muscle function in rheumatoid arthritis (RA) patients requiring treatment enhancement were compared. This multicenter, prospective, observational study (PRESENT Study) divided RA patients non-randomly into a csDMARD group (n = 100) and a b/tsDMARD group (n = 100). Changes in body composition and muscle function were examined in 80 patients in each group followed for 52 weeks. The percentages of new-onset and improved sarcopenia over 1 year were investigated. Patients in the b/tsDMARD group were divided into three groups by drug type: TNF inhibitors (n = 30), non-TNF inhibitors (n = 23), and JAK inhibitors (n = 27). Baseline median age and disease duration were 70.0 and 4.0 years, respectively. Changes in weight (24 and 52 weeks) and muscle mass (52 weeks) were significantly higher in the b/tsDMARD group (p = .035, p < .001, and p = .002, respectively). On multivariate logistic regression analysis, b/tsDMARD treatment (OR 3.21, p = .002), DAS28-ESR (OR 0.65 p = .011), and muscle mass (OR 0.90, p = .023) were independently associated with increased muscle mass at 52 weeks. The percentages of new-onset and improved sarcopenia were almost equal. There were no significant differences in the time-dependent changes (52 weeks) of clinical status, body composition, muscle function, and status of sarcopenia among TNF inhibitors, non-TNF inhibitors, and JAK inhibitors. Weight and muscle mass increased significantly more with b/tsDMARD than with csDMARD treatment. There were no differences in body composition changes by mode of action with b/tsDMARDs.

S1395 The Impact of Neutropenia on Outcomes of Crohn’s Disease Treated With Tumor Necrosis Factor Inhibitors: A Propensity Score Matched Analysis from Global Federated Health Research Network

S1395 The Impact of Neutropenia on Outcomes of Crohn’s Disease Treated With Tumor Necrosis Factor Inhibitors: A Propensity Score Matched Analysis from Global Federated Health Research Network

Disease response in rheumatoid arthritis across four biologic therapies associates with improvement in paraoxonase-1 activity and oxylipins

ObjectiveParaoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme, that has been implicated as a biomarker of cardiovascular risk in patients with rheumatoid arthritis (RA). We aimed to investigate how different...

Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin

Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington’s disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. STHdhQ7/Q7 and STHdhQ111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that STHdhQ111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was required to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.

Safety of Medications Used to Treat Autoimmune Rheumatic Diseases During Pregnancy and Lactation.

Autoimmune rheumatic diseases (ARDs) often affect women during their reproductive years, and early studies of pregnancy in these patients reported high rates of adverse outcomes. Continuation or initiation of safe and effective medications in the preconception period is beneficial for maintaining or achieving disease quiescence throughout pregnancy thereby improving both maternal and pregnancy outcomes. The European Alliance of Associations for Rheumatology, the American College of Rheumatology, and the British Society for Rheumatology have published recommendations and guidelines regarding management of ARDs during pregnancy. The American College of Obstetricians and Gynecologists and the American Gastroenterological Association have also provided guidance statements with relevant recommendations. This review provides an overview of available recommendations for medication use in ARD pregnancy, with discussion of safety considerations for maternal and fetal well-being. Medications considered compatible with pregnancy include hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine, tacrolimus, and TNF inhibitors. Methotrexate, mycophenolate, leflunomide, and cyclophosphamide should be avoided before and during pregnancy. Other medications, most of them newer, are largely discouraged for use in pregnancy due to inadequate data or concerns for neonatal immunosuppression, including non-TNF biologics and small molecule therapies. Further investigation is needed regarding effects of non-TNF biologics, biosimilars, and small molecules in pregnancy. Important efforts for the future will include improved methodologies to gather critical safety data, with consideration of inclusion of pregnant women in clinical trials, a complex and controversial issue. Long-term information on outcomes in offspring of treated women is lacking for many of these medications.

Short and Long Term Effects of The Tumour Necrosis Factor Inhibitor on The Regeneration Process of Sciatic Nerve Transection in Albino Rat

Short and Long Term Effects of The Tumour Necrosis Factor Inhibitor on The Regeneration Process of Sciatic Nerve Transection in Albino Rat

Comparative Analysis of Coagulation Activation in Rheumatoid Arthritis Patients Treated With TNF Inhibitors Versus JAK Inhibitors: A Prospective Study.

This study aims to investigate the activation of the coagulation system of RA patients and assess changes during anti-inflammatory treatment with tumor necrosis factor blockers (anti-TNF) and Janus kinase inhibitors (JAKi). Biomarkers for the coagulation system, including D-dimer, fibrinogen, prothrombin time, activated partial thrombin time, prothrombin fragment 1 + 2, thrombin-antithrombin complex (TAT), activated factor IX, antithrombin complex, and von Willebrand factor (vWF), were longitudinally measured in 83 RA patients treated with anti-TNF and 38 RA patients with JAKi. Data were collected at baseline, after 1, 3, and 6 months. The mean age was 57 (±14) years; 76% was female. The mean DAS28-CRP was 3.6 (±1.3) for anti-TNF users and 4.1 (±1.4) for JAKi users at baseline and declined in both groups. Baseline coagulation markers levels were comparable between groups. In anti-TNF users, D-dimer and fibrinogen levels significantly declined (-0.31 mg/L, p = 0.01 and -0.71 g/L, p < 0.001, respectively), whereas TAT significantly increased after 6 months follow-up (1.46 μg/L, p = 0.03) and no effect on vWF (p = 0.98). In JAKi users, vWF declined significantly during the 6 months follow-up (-37.41%, p < 0.001); additionally, there were reductions of D-dimer, fibrinogen, and TAT that did not reach significance (-0.17 mg/L, p = 0.59; -0.49 g/L, p = 0.12; and 0.68 μg/L, p = 0.27, respectively). The prothrombotic tendency in active RA declined during effective treatment with both anti-TNF and JAKi. Altogether, the biomarkers used in this study suggest that an increased VTE risk in the first 6 months due to either treatment with anti-TNF or JAKi is unlikely.

Optic Atrophy Occurring with Anti‐Tumor Necrosis Factor Alpha Therapy: A Case Report

Ocular involvement related to treatment with tumor necrosis factor alpha inhibitors is a rare adverse effect that may lead to irreversible outcomes. We illustrate through this report a case of optic atrophy under Etanercept in a patient with spondyloarthritis. The diagnosis was suspected due to visual acuity impairment, and was confirmed by ophthalmological examination. Although the TNF-blockers were discontinued and corticosteroids were administered, the follow-up examination did not reveal any improvement in visual acuity. This is a potential serious complication of TNF inhibitors that rheumatologists should recognize when monitoring patients with rheumatic diseases.

Efficacy and Safety of Tofacitinib in Patients with Psoriatic Arthritis or Ankylosing Spondylitis by Cigarette Smoking Status.

Routine care studies of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) demonstrated attenuated responses to tumor necrosis factor inhibitors in current/past versus never smokers. This post hoc analysis assessed tofacitinib efficacy and safety in patients with PsA or AS by cigarette smoking status at trial screening. Pooled data from phase 3 and long-term extension (safety only) PsA trials and phase2 and 3 AS trials were assessed by current/past versus never smoker status. Analysis included efficacy and safety data for tofacitinib 5 (PsA/AS) and 10(PsA only) mg twicedaily (BID) or placebo, and safety data in AS for tofacitinib 2 and 10 mg BID. Efficacy outcomes included American College of Rheumatology ≥ 50% responses (ACR50) and minimal disease activity (MDA) responses to month (M)6/M3 (tofacitinib/placebo) in PsA; and ≥ 40% improvement in Assessment of SpondyloArthritis international Society responses (ASAS40) and AS Disease Activity Score (ASDAS) < 2.1 responses to week (W)16 in AS. Safety was assessed to M48/W48 (PsA/AS), adjusted for treatment/smoking status/median body mass index (BMI) status/sex/trial/treatment-smoking status interaction. PsA/AS cohorts included 342/178 current/past and 572/194 never smokers. Tofacitinib efficacy was generally greater versus placebo to M3/W6 (PsA/AS), and comparable in current/past and never smokers to M6/W16 (PsA/AS). In patients receiving ≥ 1tofacitinib dose, adjusted treatment-emergent adverse event (TEAE)/serious AE (SAE)/discontinuation due to AE incidence rates (IRs) to M48 in PsA were higher in current/past versus never smokers; adjusted IRs to W48 in AS were higher in current/past versus never smokers for TEAEs, but similar for SAEs/discontinuation due to AEs. In both patients with PsA and AS, tofacitinib efficacy was greater versus placebo, and comparable across smoking categories. Adjusted IRs were higher in current/past versus never smokers for TEAEs, SAEs, discontinuation due to AEs in PsA, and for TEAEs in AS, complementing reports of associations between smoking and comorbidities in spondyloarthritis. Findings support increased surveillance/caution for patients with PsA or AS with smoking history. ClinicalTrials.gov: NCT01877668/NCT01882439/NCT03486457/NCT01976364/NCT01786668/NCT03502616.

Challenging cases in rheumatic disease pregnancy: management perspectives from reproductive rheumatologists

Pregnant women with rheumatic and musculoskeletal diseases (RMDs) have a higher risk of adverse pregnancy and perinatal outcomes compared to those without RMDs. Although evidence-based guidelines have been developed for the reproductive health care and management of these individuals, multiple areas of uncertainty exist around the diagnosis and treatment of pregnant patients with confirmed or suspected RMDs. We present a series of outpatient cases that address areas of uncertainty in the field of reproductive rheumatology. Expert opinions were elicited from rheumatologists who have expertise in the reproductive health of individuals with RMDs to build new understanding around diagnosis or treatment approaches. The cases focused on the interpretation of antiphospholipid antibodies in various clinical scenarios, diagnosis and management of nephrotic-range proteinuria during pregnancy, and the use of tumor necrosis factor inhibitors during pregnancy. Our objective was not to replace existing guidelines and classification criteria but rather to provide a range of expert opinions that rheumatologists might consider when tailoring treatment and care for patients, particularly in challenging situations with limited data.

Assessment of the relationship between hematological indices and remission duration in patients with inflammatory spondyloarthropathies treated with tumor necrosis factor inhibitors

Assessment of the relationship between hematological indices and remission duration in patients with inflammatory spondyloarthropathies treated with tumor necrosis factor inhibitors

Effect of treatment with tumor necrosis factor inhibitors on the kynurenine pathway in patients with rheumatoid arthritis

Effect of treatment with tumor necrosis factor inhibitors on the kynurenine pathway in patients with rheumatoid arthritis

Efficacy of tumor necrosis factor inhibitors for patients with psoriatic arthritis – a single-center analysis

Efficacy of tumor necrosis factor inhibitors for patients with psoriatic arthritis – a single-center analysis

Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation

Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial. Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD. Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment. These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor. This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital.

Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases.

Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases.

Review: Risk Stratification of Patients With Ulcerative Colitis for Treatment With Tofacitinib.

Lay Summary Higher age (65 years or over), long-term smoking, or a previous cardiovascular event (such as heart attack) should be considered safety risks when considering treatment with tofacitinib versus tumor necrosis factor inhibitors for people with ulcerative colitis.

Methotrexate and Tumor Necrosis Factor Inhibitors Independently Decrease Neutralizing Antibodies after SARS-CoV-2 Vaccination: Updated Results from the SUCCEED Study.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied the effects of methotrexate and tumor necrosis factor inhibitor (TNFi) on neutralization responses after COVID-19 vaccination in immune-mediated inflammatory disease (IMID). Methods: Prospective data and sera of adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and systemic lupus (SLE) were collected at six academic centers in Alberta, Manitoba, Ontario, and Quebec between 2022 and 2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between five laboratories, and each lab's results were analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for the effects of methotrexate and TNFi were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID-19 vaccinations (number/type), and infections in the 6 months prior to sampling. The adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for the ancestral strains and the Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) were RA, and the remainder were PsA, SpA, and SLE. The mean age was 57 (62.2% female). For both the individual labs and the meta-analyses, the adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval (CI) 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.