Tumor Necrosis Factor Alpha Inhibitors Research Articles

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Moderate-to-Severe Psoriasis.

Psoriasis is a common inflammatory immune disorder due to chronic activation of the adaptive and innate immune responses. Therapies for psoriasis target reducing inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-17, and interleukin-22. Patients with inflammatory disorders have reduced metabolism by cytochrome P450 enzymes in the liver. The pharmacokinetic and pharmacodynamic changes due to psoriasis also have an impact on reaching therapeutic concentrations of the drug. Pharmacokinetic and pharmacodynamic data help determine the safety and clinical considerations necessary when utilizing drugs for plaque psoriasis. A literature search was performed on PubMed and Ovid MEDLINE for the pharmacokinetic and pharmacodynamic data of oral therapies and biologics utilized for moderate-to-severe plaque psoriasis. The findings from the literature search were organized into two sections: oral therapies and biologics. The pharmacokinetic and pharmacodynamic parameters in healthy patients, patients with psoriasis, and special populations are discussed in each section. The oral therapies described in this review include methotrexate, cyclosporine, apremilast, tofacitinib, and deucravacitinib. Biologics include tumor necrosis factor-alpha inhibitors, interleukin-17 inhibitors, ustekinumab, and interleukin-23 inhibitors. Clinical considerations for these therapies include drug toxicities, dosing frequency, and anti-drug antibodies. Methotrexate and cyclosporine have a risk for hepatoxicity and renal impairment, respectively. Moreover, drugs metabolized via cytochrome P450, including tofacitinib and apremilast have decreased clearance in patients with psoriasis, requiring dose adjustments. Patients treated with therapies such as adalimumab can develop anti-drug antibodies that reduce the long-term efficacy of the drug. Additionally, overweight patients benefit from more frequent dosing to achieve better psoriasis clearance.

OP21 Spatial Transcriptomics of Pre-treatment Biopsies Revealing Molecular Maturation State and Chronic Crypt Damage, Reflecting Histological Severity, as Predictors of Primary Responsiveness to TNF-α Inhibitors in Bio-naive Ulcerative Colitis Patients

Abstract Background Biologic therapies, particularly tumor necrosis factor-alpha inhibitors (TNFi), have greatly advanced the treatment of ulcerative colitis (UC), yet significant number of patients still do not respond to these treatments. For UC management, achieving both histologic and molecular healing is crucial, highlighting the need for more comprehensive therapeutic strategies. Despite extensive research, there is a significant gap in studies that simultaneously assess histologic and molecular changes at both the crypt and lamina propria (LP) levels. Our study addresses this gap by investigating TNFi-resistant UC patients, utilizing spatial transcriptomics to discern specific cell types within histologic sections and integrating these insights to enhance understanding of UC treatment responses. Methods We evaluated 56 patients categorized into test (n=23), validation (n=31), and healthy control groups (n=2). Each underwent biopsies at the same sites before (preTx) and after treatment (postTx), as shown in Figure 1A. This study focused on a 3-month follow-up of patients who were administered TNFi as a primary biologic therapy following resistance to conventional treatments. We used digital spatial profiling to analyze gene expression in the crypt and LP, as seen in Figures 1B and 1C. We then correlated molecular data with morphological characteristics and quantitatively evaluated histologic factors, especially crypt distortion and atrophy, reported as percentages (%). Results Among the study participants, 29 were classified as responders (R) to TNFi, while 25 were non-responders (non-R). A comparative analysis of gene expression between R and non-R groups revealed a differential expression pattern: 72 genes in the crypt and 105 genes in the LP across varying histologies, as shown in Figure 1D and 1E. Notably, in the preTx samples of non-R, crypts displayed significantly lower expression of genes associated with the maturation of colonocytes, including BEST4, C10orf99, CA2, CA4, CA7, PHGR1, SLC26A2, SLC26A3, LYPD8, CLCA1, and SCNN1, compared to the R group (Figure 1F). Furthermore, when correlating spatial transcriptomic data with histomorphological features, we observed that crypt distortion and atrophy were significantly more pronounced in the non-R group than in the R group in the preTx biopsy samples (Figures 1G and 1H). Conclusion Our study's spatial profiling unveils distinct molecular and histologic features between R and non-R to TNFi among bio-naive UC patients. The evaluation of chronic histological features such as crypt distortion, and molecular maturation status, in predicting TNFi response highlights the potential of early histologic assessment in guiding biologic therapy in the UC treatment pathway.

P850 Symptomatic effectiveness of ozanimod in routine clinical care of ulcerative colitis: an interim analysis of the multicentre, prospective, noninterventional COLIBRI study

Abstract Background Ozanimod (OZA) is approved for the treatment of adults with moderately to severely active (MOD/SEV) ulcerative colitis (UC) per results of the phase 3 True North trial. Real-world data are needed to determine treatment effects in a more diverse population in clinical practice. The COLIBRI study (NCT05382715) assesses the use, effectiveness, and safety of OZA and quality of life in patients (pts) with MOD/SEV UC in a routine clinical practice setting in Germany over a period of 52 or 104 weeks. This interim analysis of COLIBRI reports baseline (BL) characteristics and evaluates the symptomatic clinical effectiveness of OZA up to Week (W) 10. Methods COLIBRI will enrol up to 380 adults with UC; the study design is shown in the Figure. Adherence to the times of visits and the diagnostic and therapeutic measures are not mandatory and will correspond to the routine processes of the respective facilities. Partial Mayo score (pMS; sum of stool frequency subscore [SFS], rectal bleeding subscore [RBS], and Physician Global Assessment), symptomatic clinical improvement, defined as either symptomatic response (decrease from BL in the combined 6-point SFS + RBS of ≥1 point and >30%, and decrease of ≥1 point in RBS or absolute RBS of ≤1 point) or symptomatic remission (RBS = 0 and SFS ≤1, and a decrease of ≥1 point from BL SFS), and symptomatic remission were assessed at W4 and W10. Data were collected by electronic case report forms and by the study-specific interface of the MyTARGET app (Kiel, Germany) for pt-related outcomes, which were evaluated throughout the study. Results Of 83 pts included in this interim analysis (BL and W4, n=58; BL and W10, n=39), the median (interquartile range) age of pts was 40 (29.0–53.0) years, 49 (59.0%) were female and 34 (41.0%) male, 80.7% had prior exposure to advanced therapies (AT), and 48.2% had prior exposure to ≥3 AT. Overall, 67.5% had prior tumor necrosis factor alpha inhibitor and 50.6% had prior vedolizumab use. BL pt characteristics are shown in the Table. In total, 76 pts with BL data had pMS data; the mean (SD) pMS at BL was 5.0 (2.2), and most pts fell within the moderate pMS category (44.9%). Mean (SD) pMS decreased from BL (5.0 [2.2]) to 3.9 (2.6) at W4 and to 3.5 (2.3) at W10. Symptomatic clinical improvement was achieved in 32.8% (19/58) and 51.3% (20/39) of pts at W4 and W10, respectively. Symptomatic remission was achieved in 22.4% (13/58) and 25.6% (10/39) of pts at W4 and W10, respectively. Conclusion This interim analysis of the German COLIBRI study showed that refractory pts with MOD/SEV UC receiving OZA achieved symptomatic effectiveness at W4 and W10 in a routine clinical practice setting.

P1028 Clinical decision support tool for vedolizumab can predict treatment persistence in Crohn's disease but not in ulcerative colitis

Abstract Background Vedolizumab (VDZ) has displayed up to 82.9% treatment persistence as a first-line biologic for ulcerative colitis (UC) and ranked third in the second line. It ranked fourth in treatment persistence as the first or second-line biological therapy in Crohn's disease (CD). Factors most commonly associated with treatment outcomes have been indicators of more aggressive disease, like refractoriness to corticosteroids and tumour necrosis factor (TNF) alpha inhibitors, elevated baseline patient-related outcomes (PROs), comorbidities in CD and faecal calprotectin. Pre-treatment prediction of response and long-term persistence could help optimise treatment in an individual patient. Methods We performed a retrospective single-centre cohort study based on the UR-CARE registry. Data for 129 patients treated with VDZ from July 2016 until April 2023 were analysed. A validated clinical decision support tool (CDST) for CD and UC was used to stratify patients according to the probability of response to VDZ. We used Kaplan-Meier survival curves to analyse treatment persistence at week 52, depending on the CDST group for CD and UC. The association between the CDST group and the optimisation of VDZ therapy was evaluated using the chi2 test. Results The study included 57 CD patients, median age 34 years, 38.6% male, and 72 UC patients, median age 32.1 years, 59.7% male. Patients with CD had longer disease duration (4.1 years) than UC patients (2.6 years). 33.3% of CD patients had ileo-colonic disease, 24.6% had upper GI involvement, 33.3% had fistulising disease, and 56.1% had prior surgery. 63.9% of patients with UC had pancolitis, and 34.7% had concomitant corticosteroids at baseline. Before VDZ, more than half of patients were exposed to TNF alpha inhibitors in both CD and UC (57.9% and 52.8%, respectively). We found significantly higher treatment persistence in CD patients stratified into groups with intermediate (group 1) and high (group 2) probability of response, according to CDST compared to the group with low (group 0) probability of response. The VDZ therapy was discontinued in 76.9%, 28.6% and 6.3% of patients within CDST groups 0, 1, and 2, respectively. The association was statistically significant (p < 0.001). In UC, however, we could not confirm any significant difference in treatment persistence between CDST groups. The VDZ therapy was discontinued in 50.0%, 34.9%, and 21.9% in groups 0, 1, and 2, respectively. While the trend between discontinuation of the VDZ and CDST groups can be observed, the association was not statistically significant (p = 0.165). Conclusion In our study, treatment persistence for VDZ could be predicted using CDST for CD, but not for UC.

Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti-PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.

Infections in the era of immunobiologicals

Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.

Risk of Primary Gastrointestinal Lymphoma in Patients With Inflammatory Conditions Exposed to Tumor Necrosis Factor Alpha Inhibitors and Immunomodulators: A Case-Control Study.

The aim of this case-control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions. Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn's disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs. Twenty PGIL cases matched with 60 controls were followed for a mean 9.9 ± 6.9 and 9.7 ± 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5 ± 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR] = 2.6; 95% confidence interval [CI] 0.69-11.01; P = .18), but with use of TNFI in combination with thiopurines (OR = 8.93; 95% CI 1.43-80.25; P = .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002-5.713); P = .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (OR = 6.32; 95% CI 1.55-37.05; P = 0.006) to develop PGIL. TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.

Switching related to inefficacy in biologics and targeted synthetic therapies for psoriatic arthritis: a comparative real-life study.

Switching between therapies is a recommended strategy for psoriatic arthritis (PsA) patients who experience treatment failure; however, studies including real-life data are scarce. To assess the incidence rate (IR) of switching between biologics and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) due to inefficacy in PsA, and to compare the risk of switching due to inefficacy across different b/tsDMARDs groups. A longitudinal retrospective study, spanning from 2007 to 2022, was conducted on patients with PsA treated with b/tsDMARDs at an outpatient rheumatology clinic. The primary outcome was switching between b/tsDMARDs due to inefficacy. The independent variable was the exposure to b/tsDMARDs during follow-up. As covariates, clinical, treatment-related, and sociodemographic variables were considered. Survival techniques were run to estimate the IR of switching due to inefficacy per 100 patients*year and confidence interval at 95% (95% CI). Cox multivariate regression analyses were run to assess the risk of b/tsDMARDs switching due to inefficacy, expressed as hazard ratio (HR) and 95% CI. In all, 141 patients were included, with 893.09 patients*year follow-ups. 52.48% of them were females in their fifties. In total, 262 courses of treatment were recorded. During the study period, 56 patients presented 121 switches and 103 related to inefficacy (IR: 11.53 (9.51-13.98)). Tumor necrosis factor-alpha inhibitors (TNFi) showed the lowest IR. In the bivariate analysis, all b/tsDMARDs had more risk of switching compared to TNFi (HR: anti-lL-17 vs TNFi: 2.26 (1.17-4.36); others vs TNFi: 3.21 (1.59-6.45)); however, this statistical significance was no longer present in the multivariate analysis once adjustments were made for the covariates. Still, the final model achieved statistical significance in the following variables: gender, clinical symptoms, prescription year, therapy courses, glucocorticoids, and sulfasalazine. In this study, we did not find differences in the rate of switching due to inefficacy among different groups of b/tsDMARDs. Other concomitant treatments, sociodemographic, and clinical variables were identified as risk factors for switching due to inefficacy.

Severe Antiphospholipid Syndrome and Diffuse Glomerulonephritis After Adalimumab Treatment in a Patient With Ulcerative Colitis

Tumor necrosis factor alpha inhibitors (TNFi) are biological drugs used worldwide to treat various autoimmune disorders. Paradoxically, TNF‐α antagonists can also induce autoimmune diseases being systemic vasculitis, systemic lupus erythematosus, and psoriasis, the most common. We present a 22‐year‐old woman with ulcerative colitis (UC) who was started on adalimumab 40 mg subcutaneously every 2 weeks. After two doses of adalimumab, she developed gangrene of all toes and acute kidney injury requiring hemodialysis. Skin biopsy showed thrombi in the small vessels of the dermis. Renal biopsy disclosed diffuse proliferative glomerulonephritis (GN) and acute tubulointerstitial nephritis. Serologic work‐up showed positive IgG anticardiolipin (ACL) antibodies and low C3 levels. Antinuclear, anti‐dsDNA, anti‐Smith, anti‐SSA, anti‐SSB, anti‐RNP, antineutrophil cytoplasmic antibodies, ACL (IgA and IgM), and anti‐β2‐glycoprotein I (IgG, IgM, and IgA) antibodies were not elevated. Lupus anticoagulant test and cryoglobulins were negative. Adalimumab was discontinued, and she was treated with enoxaparin, intravenous (IV) methylprednisolone pulse, IV cyclophosphamide, and plasmapheresis followed by maintenance therapy with warfarin, prednisone, azathioprine, and hydroxychloroquine. She did not have further thrombotic events, and the acute kidney injury completely resolved. ACL IgG antibodies decreased to normal levels, and repeated tests were negative. After 7 years, anticoagulation and immunosuppressive drugs were discontinued. During a follow‐up of 24 months, she remained in complete clinical remission. This report highlights the occurrence of autoimmune disorders induced by TNFi. Thus, careful monitoring of adverse immune reactions to TNFi is highly recommended.

Etanercept induced erectile dysfunction

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial spine. Etanercept is a Tumor necrosis factor-alpha inhibitor (anti-TNF) that is widely used in the treatment of AS. The most common side effects of etanercept are infection, rash, and injection site reaction. Here, we reported an adverse event probably associated with etanercept. Case Presentation: A 30-year-old male patient with AS initiated etanercept due to uncontrolled back pain despite adequate doses of non-steroidal anti-inflammatory drugs. He developed erectile dysfunction (ED) within 1 month of etanercept treatment. ED disappeared after switching to secukinumab. Conclusion: There is limited data on the potential effects of anti-TNF on sexual function. ED might be a rare side effect of etanercept that resolves upon discontinuation of the drug. Secukinumab might be considered as an option in case of etanercept induced ED. Even though ED is not a life-threatening side effect, switching medications could significantly improve patients' quality of life.

Cardiovascular Adverse Events Associated with Tumor Necrosis Factor-Alpha Inhibitors: A Real-World Pharmacovigilance Analysis.

Evidence regarding the association between various tumor necrosis factor-α (TNF-α) inhibitors and cardiovascular adverse events (AEs) is both limited and contradictory. A retrospective pharmacovigilance study was conducted using the FDA Adverse Event Reporting System (FAERS) database. Cardiovascular AEs associated with TNF-α inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) were evaluated using a disproportionality analysis. To reduce potential confounders, adjusted ROR and subgroup analyses were performed. After excluding duplicates, 9,817 cardiovascular reports were associated with the five TNF-α inhibitors. Only adalimumab had positive signals for myocardial infarction (ROR=1.58, 95%CI=1.51-1.64) and arterial thrombosis (ROR=1.54, 95%CI=1.49-1.58). The remaining four TNF-α inhibitors did not show a risk association with any type of cardiovascular event. Further analyses of specific indication subgroups and after adjusting for any confounding factors demonstrated that adalimumab was still significantly associated with cardiovascular events, especially in patients with psoriasis (adjusted ROR=2.16, 95%CI=1.95-2.39). This study revealed that adalimumab was the only TNF-α inhibitor associated with an elevated risk of thrombotic cardiovascular AEs, whereas the other four TNF-α inhibitors did not show any risk effect. However, given the limitations of such pharmacovigilance studies, it is necessary to validate these findings in prospective studies in the future.

Study of thyroid disorders in ankylosing spondylitis patients on anti-tumor necrosis factor treatment

Abstract: BACKGROUND: Ankylosing spondylitis (AS) is a systemic rheumatic disease characterized mainly by involvement of sacroiliac joints and axial skeleton. Tumor necrosis factor-alpha (TNF-α) inhibitors are biologic agents which are Food and Drug Administration approved to treat AS and also act as a key factor in the treatment of autoimmune thyroid disease. OBJECTIVE: This study aimed to evaluate the thyroid gland disorders (functions and thyroid autoantibodies) in AS patients on anti-TNF-α biologics and their relation to disease activity. PATIENTS AND METHODS: This comparative cross-sectional study included 75 AS patients classified into two groups: Group I: treated with NSAIDs (n = 30) and Group II: treated with anti-TNF-α biologics (n = 45). Thyroid function tests, thyroid autoantibodies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and human leukocytic antigen B27 were measured. AS disease activity was assessed by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) scores. Thyroid ultrasonography was used to detect any thyroid gland nodularity and echogenicity. RESULTS: There were significant differences between both groups regarding BASDAI (P = 0.005), CRP (P = 0.005), thyroid-stimulating hormone (TSH) (P = 0.001), and anti-thyroid peroxidase (anti-TPO) (P = 0.007). A significant difference was found regarding the thyroid status, with more normal thyroid and more hyperthyroid patients in the anti-TNF-treated group (P = 0.003). There were statistically significant positive correlations between BASDAI and CRP (P = 0.007), TSH (P = 0.004), and thyroid anti-TPO antibody (P = 0.008) in the anti-TNF-treated patients. By ultrasound examination of the thyroid gland, 75.6% of the anti-TNF group had normal thyroid gland compared to 56.6% of the other group, and the reported nodules were mostly of benign TIRADS classification. Comparing different subgroups of thyroid nodularity with different treatment regimens revealed significant differences in BASDAI and different laboratory investigations in favor of the anti-TNF-treated patients. CONCLUSION: From this cohort study, we can conclude that thyroid autoimmune disease and thyroid nodules in AS patients can be controlled by treatment with anti-TNF-α biologic drugs better than NSAIDs alone.

Increased neutrophil extracellular trap formation in oligoarticular, polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis: biomarkers for diagnosis and disease activity.

Neutrophil extracellular traps (NETs) are important factors in initiating and perpetuating inflammation. However, the role of NETs in different subtypes of juvenile idiopathic arthritis (JIA) has been rarely studied. Therefore, we aimed to explore the ability of JIA-derived neutrophils to release NETs and the effect of TNF-α (tumor necrosis factor-alpha) inhibitors on NET formation both in vitro and in vivo, and evaluate the associations of NET-derived products with clinical and immune-related parameters. The ability of neutrophils to release NETs and the effect of adalimumab on NET formation was assessed via in vitro stimulation and inhibition studies. Plasma NET-derived products were detected to assess the incidence of NET formation in vivo. Furthermore, flow cytometry and western blotting were used to detect NET-associated signaling components in neutrophils. Compared to those derived from HCs, neutrophils derived from patients with oligoarticular-JIA, polyarticular-JIA and enthesitis-related arthritis were more prone to generate NETs spontaneously and in response to TNF-α or PMA in vitro. Excessive NET formation existed in peripheral circulation of JIA patients, and elevated plasma levels of NET-derived products (cell-free DNA and MPO-DNA complexes) could accurately distinguish JIA patients from HCs and were positively correlated with disease activity. Multiple linear regression analysis showed that erythrocyte sedimentation rate and TNF-α levels were independent variables and were positively correlated with cell-free DNA concentration. Notably, TNF-α inhibitors could effectively prevent NET formation both in vitro and in vivo. Moreover, the phosphorylation levels of NET-associated kinases in JIA-derived neutrophils were markedly increased. Our data suggest that NETs might play pathogenic roles and may be involved in TNF-α-mediated inflammation in JIA. Circulating NET-derived products possess potential diagnostic and disease monitoring value. Furthermore, the preliminary results related to the molecular mechanisms of NET formation in JIA patients provide a theoretical basis for NET-targeted therapy.

Impact of tobacco smoking on response to tumor necrosis factor-alpha inhibitor treatment in a sample of Iraqi patients with ankylosing spondylitis

Impact of tobacco smoking on response to tumor necrosis factor-alpha inhibitor treatment in a sample of Iraqi patients with ankylosing spondylitis

A case report on new-onset peritoneal tuberculosis in ankylosing spondylitis patient on adalimumab

Adalimumab, a widely employed tumor necrosis factor-alpha inhibitor for autoimmune diseases, raises concern about reactivating latent tuberculosis (TB) and new-onset TB. Despite its established efficacy in managing inflammation, clinicians must recognize and manage adalimumab-induced TB promptly to minimize associated morbidity. This case report explores guidelines for TB screening in adalimumab-treated patients, utilizing interferon-gamma release assays and tuberculin skin tests, and discusses treatment considerations. Increased TB incidence in adalimumab-treated patients necessitates vigilant screening for latent TB before therapy initiation. Therapeutic decisions must balance the need for continuing immunosuppressive therapy against the potential risks of uncontrolled TB. Diagnostic challenges arise from atypical presentations and the intricate interplay between adalimumab therapy and TB manifestations. Given adalimumab’s expanding use, clinicians should be mindful of potential TB reactivation, emphasizing thorough screening, diagnosis, and management for improved patient care and safety amidst immunosuppressive therapies. Here, we are presenting the case of adalimumab-induced peritoneal TB.

Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats.

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1β-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.

Tumor Necrosis Factor Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an increased risk of cardiovascular events, due to the complex interplay between traditional and disease-related risk factors. Chronic inflammation and persistent disease activity are the key determinants of this risk, but despite great improvement in the disease management and prognosis, cardiovascular events are still the main cause of morbidity and mortality in RA cohorts1. In the last decades, the advent of new biological and targeted-synthetic DMARDs was accompanied by an improvement in disease activity control, but the role of each class of drugs on CVD risk is still a matter a debate. Since their approval for RA treatment, tumor necrosis factor alpha (TNFα) inhibitors have been widely investigated to better understand their effects on cardiovascular outcomes. The hypothesis that the reduction of chronic inflammation with any treatment may reduce the cardiovascular risk has been recently confuted by the direct comparison of TNFα-inhibitors and JAK inhibitors in patients with RA and coexisting risk factors for cardiovascular disease. The aim of this literature review is to add to the available evidence to analyze the relationship between TNFα-inhibitors and CVD risk in patients with RA and also provide some clinical scenarios to better explain the treatment dilemmas. In particular, while data on major cardiovascular events and thromboembolism seem consistent with an inflammation-mediated benefit with TNFα-inhibitors, there remain concerns about the use of this class of bDMARDs in patients with chronic heart failure.

Enhancement of cardiac angiogenesis in a myocardial infarction rat model using selenium alone and in combination with PTXF: the role of Akt/HIF-1α signaling pathway

Ischemic heart diseases such as myocardial infarction (MI) are a global health problem and a leading cause of mortality worldwide. Angiogenesis is an important approach for myocardial healing following ischemia. Thus, this study aimed to explore the potential cardiac angiogenic effects of selenium (Se), alone and in combination with the tumor necrosis factor-alpha inhibitor, pentoxifylline (PTXF), via Akt/HIF-1α signaling. MI was induced in rats using two subcutaneous doses of isoprenaline (ISP) at a 24-h interval (150 mg/kg). One week later, rats were orally given Se (150 µg/kg/day), PTXF (50 mg/kg/day), or Se/PTXF combination. ISP-induced myocardial damage was evident by increased HW/TL ratios, ST segment elevation, and increased serum levels of CK-MB, LDH, and troponin-I. ISP increased the cardiac levels of the lipid peroxidation marker MDA; the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the pro-apoptotic protein Bax and caspase-3. In contrast, the cardiac levels of the antioxidant markers GSH and SOD and the anti-apoptotic marker Bcl-2 were reduced. Furthermore, ISP markedly increased the cardiac levels of p-Akt and HIF-1α proteins and the cardiac gene expression of ANGPT-1, VEGF, and FGF-2. Treatment with Se both alone and in combination with PTXF ameliorated the ISP-induced myocardial damage and further increased cardiac angiogenesis via Akt/HIF-1α signaling. Se/PTXF combined therapy was more beneficial than individual treatments. Our study revealed for the first time the cardiac angiogenic effects of Se both alone and in combination with PTXF in myocardial infarction, suggesting that both may be promising candidates for clinical studies.Graphical

Cutaneous squamous cell carcinoma tumor accrual rates in immunosuppressed patients with autoimmune and inflammatory conditions: A retrospective cohort study

Immunosuppression is a known risk factor for the development of cutaneous squamous cell carcinoma (CSCC), especially in solid organ transplant recipients and chronic lymphocytic leukemia. However, this risk is less well defined in autoimmune and inflammatory conditions. Assess the impact that disease-type, duration of immunosuppression, and systemic medications have on CSCC accrual rates, defined as the number of CSCCs a patient develops per year, in autoimmune and inflammatory conditions. Retrospective review of 94 immunosuppressed (rheumatoid arthritis: 31[33.0%], inflammatory bowel disease: 17[18.1%], psoriasis: 11[11.7%], autoimmune other (AO): 24[25.5%], inflammatory other: 21[22.3%]) and 188 immunocompetent controls to identify all primary, invasive CSCCs diagnosed from 2010 to 2020. Immunosuppressed patients had higher CSCC accrual rates than immunocompetent controls (0.44±0.36): total cohort (0.82±0.95, P<.01), rheumatoid arthritis (0.88±1.10, P<.01), inflammatory bowel disease (0.94±0.88, P<.01), psoriasis (1.06±1.58, P<.01), AO (0.72±0.56, P<.01), and inflammatory other (0.72±0.61, P<.01). There was an association between increased tumor accrual rates and exposure to systemic medications including, immunomodulators, tumor necrosis factor-alpha inhibitors, non-tumor necrosis factor inhibitor biologics, and corticosteroids, but not with number of systemic medication class exposures or duration of immunosuppression. Retrospective, singlecenter study. Patients with autoimmune and inflammatory conditions accrue CSCCs at higher rates than immunocompetent patients.

Persistence of Janus-kinase (JAK) inhibitors in rheumatoid arthritis: Australia wide study

BackgroundTo compare persistence of disease-modifying antirheumatic (DMARDs), with a focus on Janus kinase (JAK) inhibitors in Australian rheumatoid arthritis (RA) patients. MethodsA retrospective observational study was conducted among 4,521 RA patients (females n=3,181 [70.4%]), using data from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset, aged ≥18 years and initiating a DMARD between 2011 to 2021. Kaplan-Meier analysis was used to estimate persistence rates, defined as occurrence of 6 months gap after the end of a drug dispensing. ResultsTwelve-month persistence rates were 72% for upadacitinib, 61% for baricitinib, 58% for subcutaneous tumor necrosis factor-alpha inhibitors (TNFi), 55% for tocilizumab, 53% for tofacitinib, and 49% for abatacept. Median treatment persistence was not reached for upadacitinib (n=574) and baricitinib (n=553); and was 15.0 months for tofacitinib (95% CI 13.5–19.5), 20.5 months for TNFi (95% CI 19.0–22.4), 19.1 months for tocilizumab (95% CI 17.9–23.6), and 12.5 months for abatacept (95% CI 10.4–14.9). Persistence rates on first-line JAK inhibitors were 68% for upadacitinib and baricitinib and 55% for tofacitinib, and 49% for TNFi, 55% for abatacept, and 57% for tocilizumab; rates were sustained for upadacitinib, TNFi, and tocilizumab but dropped to 59% for baricitinib and 47% for abatacept in the second-line treatment. For each b/tsDMARD, persistence rates were higher when combined with methotrexate or other conventional synthetic DMARDs. The median oral glucocorticoid dose decreased from 4.3 mg/day (range:0–40) to 2.3 mg/day (range:0–22) over 2 years. Changes were significant for all RA DMARDs, tofacitinib and baricitinib combined (1–2 years post initiation only), TNFi, abatacept, and tocilizumab. ConclusionsIn a real-world setting, we showed highest persistence rates on upadacitinib, followed by baricitinib and then TNFi therapy and was improved by co-therapy. All agents appeared to be corticosteroid sparing.