anti-TNF Drugs Research Articles

Correlation Between Ultrasonographic Response and Anti-Tumor Necrosis Factor Drug Levels in Crohn's disease.

Ultrasound is valuable in tight control algorithms for Crohn's disease (CD). However, the correlation between ultrasonographic response and anti-tumor necrosis factor (TNF) drug levels remains unknown. Elucidating this correlation would be helpful in optimizing the use of anti-TNF drugs. Thus, the authors aimed to investigate this correlation. Between June 2020 and June 2021, all patients with CD who completed anti-TNF induction therapy were retrospectively included. Ultrasound was performed at week 0 and week 14, and proactive therapeutic drug monitoring of anti-TNF drugs was performed at week 14. The receiver operating characteristic (ROC) curve was used in the correlation analysis. Ninety-two patients (60 treated with infliximab and 32 with adalimumab) were included. At week 14, an ultrasonographic response was detected in 43 patients. Patients with ultrasonographic response had significantly higher median drug levels (5.9 mcg/mL for infliximab; 18.2 mcg/mL for adalimumab) than those without (0.9 mcg/mL for infliximab, P < 0.001; 4.8 mcg/mL for adalimumab, P < 0.001). The ROC curve showed a significant correlation between ultrasonographic response and anti-TNF drug levels (area under the curve = 0.79 for infliximab, P < 0.001; area under the curve = 0.86 for adalimumab, P < 0.001). The optimal cut-off values for infliximab and adalimumab correlated with ultrasonographic response were 5.0 and 10.5 mcg/mL, respectively. An incremental increase was observed in ultrasonographic response with higher anti-TNF drug levels. Higher anti-TNF drug levels are associated with an increased likelihood of ultrasonographic response in patients with CD.

S863 Impact of Race on ANTI-TNF Immunogenicity in Patients with Inflammatory Bowel Disease

Introduction: Immunogenicity is a major contributor to anti-tumor necrosis factor (anti-TNF) treatment failure in inflammatory bowel disease (IBD). Immunomodulator and anti-TNF combination therapy is associated with a decreased risk of immunogenicity. Anti-TNF immunogenicity was recently linked to HLA-DQA1*05 genotype. This study aims to determine the impact of race on rates of immunogenicity and treatment outcomes of IBD pts on anti-TNF combination therapy. Methods: This was a single-center, retrospective study of IBD pts who have been treated with immunomodulators and anti-TNF combination therapy between 2012 and 2020. Our primary outcomes were the rates of anti-TNF antibody formation and mean anti-TNF drug levels between Caucasian group(CG) and non-Caucasian group(NCG) on combination therapy. Secondary outcomes included steroid-free clinical remission (SFCR), endoscopic remission (ER) (absence of ulcers/erosions in CD and Mayo endoscopic score ≤ 1 for UC), & normal serum C-reactive protein (CRP) (defined as ≤ 5. mg/L). Continuous variables were analyzed using unpaired student’s t-test. Categorical variables were analyzed using a chi-square test. Results: A total of 124 pts were included (CD; 68.5%, UC; 27.4%, indeterminate colitis; 3.2%, pouchitis; 0.9%). The median age was 32 years (range 13-69), and 54.8% were male. A total of 87 pts were on infliximab & 37 pts were on adalimumab. Combination therapy with thiopurine was employed in 87.1% while 12.9% were on methotrexate. A total of 85 pts were self-identified as Caucasian. There were no significant differences between CG vs NCG in terms of baseline and disease characteristics (Table). Anti-TNF antibody formation was observed in 32.9% of pts in the CG, and 20.5% of pts in the NCG (p=0.16). Mean anti-TNF drug levels were lower in the CG at 15.4 ± 14.5 µg/mL vs. the NCG at 22.7 ± 15.1 µg/mL (p=0.01). SFCR was observed in 61.2% vs. 58.9% (p=0.82) in CG vs. NCG, respectively. In CG 42.4% vs. 33.3% in NCG (p=0.34) discontinued anti-TNF treatment during follow-up. ER was observed in 45.9 % vs 51.3% (p=0.44), and normal CRP was observed in 51.8% vs. 58.9% (p=0.28) in CG vs. NCG, respectively. Conclusion: In our cohort, Caucasian pts on anti-TNF combination therapy for IBD had significantly lower anti-TNF drug levels as compared to the non-Caucasian group. However, there was no significant difference between rates of anti-TNF antibody formation and clinical outcomes between the groups. Larger studies are needed to clarify impact of race on anti-TNF therapy. Table 1. - Comparison of Characteristics Between Caucasian vs. Non-Caucasian Race Caucasian (n=85), n (%), mean (SD) Non-Caucasian (n=39), n (%), mean (SD) P-value 34.7 (13.7) 34.7 (11.7) 0.98 47 (55.3) 21 (53.9) 0.88 7 (8.2) 6 (15.4) 0.23 36.4 (27.1) 41.9 (31.8) 0.35 0.07 53 (62.4) 32 (82.1) 29 (34.1) 5 (12.8) 2 (2.3) 2 (5.1) 1 (1.2) 0 21 (24.7) 15 (38.5) 0.12 24 (28.2) 14 (35.9) 0.81 10 (11.8) 6 (15.4) 0.77 61 (71.8) 26 (66.7) 0.56 69 (81.2) 29 (74.4) 0.39 12.5 (21.4) 6.8 (7.6) 0.15 3.9 (0.6) 4.1 (0.4) 0.16 *Data missing for 68 patients.**Data missing for 42 patients.Abbreviations: Anti TNF, anti-tumor necrosis factor; CRP, C reactive protein.

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn's Disease.

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn’s disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD.

CNVs Associated with Different Clinical Phenotypes of Psoriasis and Anti-TNF-Induced Palmoplantar Pustulosis.

Background: Psoriasis can present different phenotypes and could affect diverse body areas. In contrast to the high effectiveness of biological drugs in the treatment of trunk and extremities plaque psoriasis, in palmoplantar phenotypes and in plaque scalp psoriasis, these same drugs usually have reduced efficacy. Anti-TNF drugs could induce the appearance of palmoplantar pustulosis (PPP) in patients with other inflammatory diseases. The objective of this study is to identify if there are DNA Copy Number Variations (CNVs) associated with these different clinical phenotypes, which could justify the differences found in clinical practice. Moreover, we intend to elucidate if anti-TNF-induced PPP has a similar genetic background to idiopathic PPP. Methods: Skin samples were collected from 39 patients with different patterns of psoriasis and six patients with anti-TNF-induced PPP. The CNVs were obtained from methylation array data (Illumina Infinium Human Methylation) using the conumee R package. Results: No significant CNVs were found between the different phenotypes and the locations of psoriasis compared. Nevertheless, we found two significant bins harboring five different genes associated with anti-TNF-induced PPP in patients with a different background other than psoriasis. Conclusions: Our results may help to predict which patients could develop anti-TNF-induced PPP.

Differential Effects of Anti-TNFα and Anti-α4β7 Drugs on Circulating Dendritic Cells Migratory Capacity in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4β7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin β7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.

Effectiveness of Golimumab as Second Anti-TNFα Drug in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Axial Spondyloarthritis in Italy: GO-BEYOND, a Prospective Real-World Observational Study.

In this prospective observational study, data were collected from 34 rheumatology clinics in Italy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) who started golimumab (GLM) as a second anti-TNFα drug. The primary objective was to evaluate the effectiveness of GLM after 6 months. Changes in quality of life using the EQ-5D-5L were also assessed. A total of 194 patients aged 53.2 ± 12 years started GLM as a second anti-TNF drug: 39 (20.1%) with RA, 91 (46.9%) with PsA and 64 (32.9%) with axSpA. After 6 months of GLM treatment, 68% of RA patients achieved low disease activity (LDA; DAS28-CRP ≤ 3.2), 31.9% of PsA patients achieved minimal disease activity and 32.5% of axSpA patients achieved LDA (ASDAS-CRP < 2.1). Good/moderate EULAR response was achieved in 61.9% and 73.8% of patients with RA and PsA, respectively, and 16% of axSpA patients achieved a 50% improvement in BASDAI. Across all indications, improvements in disease activity measures and EQ-5D-5L domains were observed over 6 months. The main reasons for GLM interruption were lack/loss of efficacy (7.2%) or adverse events (2%). This study confirms the effectiveness of GLM as a second-line anti-TNF for the treatment of RA, PsA and axSpA in a real-world setting in Italy.

Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.

This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients. A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment. Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073). Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

Use of biologics for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated. We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008-2021). In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year. Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common.

POS1273 EVALUATION OF THE SAFETY PROFILE OF COVID-19 VACCINES IN CHILD PATIENTS USING BIOLOGICAL THERAPY

BackgroundCoronavirus vaccines have been widely applied all over the world after the coronavirus pandemic. There are inactivated vaccines and mRNA vaccines in our country. There is no clear guideline for the vaccination programs of patients receiving immunosuppressive therapy, especially childhood.ObjectivesFor this reason, we wanted to evaluate the frequency of side effects developed after covid-19 vaccine in pediatric patients diagnosed with rheumatic disease using biological therapy and nonbiologic disease modifiying drugsMethodsA total of 226 patients over the age of 12, who were followed up in the pediatric rheumatology clinic of the University of Health Sciences, Umraniye Training and Research Hospital, using biological therapy and were vaccinated against Covid-19, were included in the study. The standard questionnaire forms were filled in face-to-face after each administration for both vaccines. The patient, who had any serious side effects, was followed up in the hospital.ResultsOf the 226 patients included in the study, 97 were male and 128 were female. Their mean age was 16.4 + 2.4. It was determined that 88.4% (n=200) of the patients had mRNA vaccine and 11.6% (n=26) had inactivated vaccine. 105 of the patients were using biologic drugs during vaccination. Of these, 63 (27.9%) patients were treated with anti-TNF drugs (46 adalimumab, 10 etanercept, 6 inflixmab), 32 patients were anti-il-1 (30 canakinumab, 2 anakirna), 4 patients were anti-il-6, 3 patients were anti-il-17, 3 patient was receiving abatacept and 1 patient was receiving rituximab. 121 patients were using DMARDs. Of these, 61 were using colchicine. 26.5% (n=60) of the patients had covid infection before vaccination. Side effects were observed in 180 of our patients. No side effects were observed in 46 patients. Pain at the injection site was the most common among them, 72.6% (n=164). Headache was seen in 16.8% (n=38) of the patients, myalgia in 18.1% (n=41), fever in 16.4% (n=37) and arthralgia in 6.6% (n=15). The frequency of serious adverse events was determined as 0.9%(n=2). Both patients were followed up in the ward. When the patients were compared in terms of covid infection and gender, there was no significant difference in the frequency of side effects. When the vaccines were compared, the incidence of side effects in the mRNA vaccine was statistically significantly higher (p=0.001). Pain at the injection site was significantly less frequent in the inactivated vaccine (p=0.004). In terms of drug distribution, there was no significant difference in the frequency of side effects between patients using biologic drugs and DMARDs. p=0.004) There was no statistically significant difference in the frequency of side effects when the patients using dmard were compared as colcicine and other dmards.ConclusionIn our study, we have shown that the use of vaccines in individuals with adolescent rheumatological diseases is safe and that the biological treatments used by the patients do not cause an increase in the risk of vaccine side effects. In addition; We have shown in our study that the side-effect profile of the inactivated vaccine used in our country is milder than the mRNA vaccine, and that it affects daily life less. Another result of our study was that anti-TNF drugs could cause a decrease in pain sensation due to the relationship of anti-TNF with pain pathways.

OP0268 COMPARISON OF MAJOR CARDIOVASCULAR AND THROMBOEMBOLIC EVENTS IN SAFETY REPORTS BETWEEN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH JAK INHIBITORS VERSUS ANTI-TNF: RESULTS FROM VigiBase

BackgroundRecently, awareness has raised regarding JAK inhibitor safety in rheumatoid arthritis (RA), in particular with tofacitinib. Indeed, in a trial involving more than 4,000 patients (ORAL Surveillance), a numerically higher number of major cardiovascular events (MACEs) in patients treated with tofacitinib compared to anti-TNF (1), and a higher risk of venous thromboembolic events (VTE) in patients treated with tofacitinib 10mg twice a day compared to patients treated with tofacitinib 5mg twice a day or anti-TNF was observed. This increased risk of MACEs was also suspected in another study performed on American Health databases (2). Recently, the FDA extended warnings and use’s recommendations to other JAK-inhibitor drugs (3).ObjectivesTo corroborate these safety warnings, we compared the reporting MACEs and VTEs with JAK inhibitors versus anti-TNF alpha drugs from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database (VigiBase).MethodsWe selected reports in Vigibase of patients aged between 18 and 75 years, between 01/01/2011 and 12/31/2020, with JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib) or anti-TNF (etanercept, adalimumab, infliximab, certolizumab pegol, golimumab) with a diagnosis of RA. In these reports we selected MACEs including myocardial infarction, strokes and cardiovascular deaths and VTE including deep venous thromboses (DVT) and pulmonary embolisms (PE). Characteristics of reports including age of patients, country of declaration, drug involved, co-reported drugs, and type of event were described. The reporting risk was investigated using disproportionality analyses and expressed as Reporting Odds Ratios (ROR) with 95% Confidence Interval (95%CI). A sensibility analysis was performed stratifying by age category (≥ 65 years, ≥ 50 years), and by sex.ResultsOf the 11,455,891 reports in patients aged between 18 and 75 years in the period of interest, 39,097 of reports were for a JAK-inhibitor in RA (mean age 60.6 years, SD:16.3) and 231,860 of reports were for an anti-TNF in RA (mean age: 57.2 years, SD: 13.0). Most of the reports came from USA and Canada (respectively 77.4% and 12.5% for JAK-inhibitor and 86.4% and 2,6% for anti-TNF). Among the reports, 611 (1.6%) in JAK-inhibitor treated patients and 3240 (1.4%) in anti-TNF treated patients were MACEs while 341 (0.9%) in JAK-inhibitors and 571 (0.2%) in anti-TNF treated patients were VTE. Disproportionality analyses identified an increased risk of reporting VTE events in JAK-inhibitors compared to anti-TNF (DVT: ROR = 3.99 [95%CI: 3.15-5.04], PE: ROR = 3.47 [2.90-4.13], Figure 1). This risk was not modified after stratification by age or sex. No increased ROR for MACE was found.Figure 1.ConclusionBased on real-world data, the analysis did not identify an increase of declaration of MACEs with JAK-inhibitor compared to anti-TNF whereas we could observe more than three times declarations of VTE in Vigibase with JAK-inhibitors compared to anti-TNF.

Effects of anti-TNF biologic drugs on uveitis severity in Behçet patients: systematic review and Meta-analysis.

To investigate effects of anti-TNF biologic drugs on uveitis severity (comparing visual acuity logMAR levels) in Behçet patients. Three databases PubMed, Scopus, and the Web of Science were searched for qualified papers focusing on the anti-TNF-α factors treatment in Behçet's disease (BD)-associated uveitis. Studies that were designed pre and post anti-TNF drug treatment, were selected. After determining the search strategy for this study, the relevant data were extracted. The initial search was performed in the target databases and a total of about 1458 articles were found. Fifteen articles were selected for systematic review and only 12 of them had inclusion criteria for Meta-analysis (with visual acuity data). The mean dose of prednisolone before and after biological treatments was reported in 5 studies (28.56 and 7.56 mg/kg, respectively). Also, the preliminary results indicate a significant reduction in visual acuity logMAR levels (MD=-1.5 IU/L, 95%CI: -2.1, -0.01). Biological drugs significantly reduce the dose of prednisolone and affect visual acuity values.

Treatment Adherence of Anti-TNF Drugs in the Patients with Inflammatory Bowel Disease: A Scale Development Study.

This work studies the validity and reliability of the Anti-TNF Alpha Treatment Adherence Scale, which has newly been developed to measure the compliance of inflammatory bowel disease patients using the anti-TNF alpha agents that are widely used in gastroenterology and rheumatology clinics. The study group consisted of 165 irritable bowel disease patients aged 18 years and above who were using anti-TNF alpha drugs. After creating a question pool with 40 items, the pilot study was applied with 70 patients. SPSS 25.0 and AMOS programs were used. Item-total correlation coefficients, Cronbach's alpha and test-retest analysis, missing data, extreme value, normality, 27% sub- upper item discrimination analysis, and exploratory and confirmatory factor analyses were used. The factor structure of the scale was examined with exploratory and confirmatory factor analyses and the contribution of these components to the total variance was measured as 74.21%. The Anti-TNF Alpha Treatment Adherence Scale was found in relation to the scale structure consisting of 12 items and 4 sub-dimensions. According to the first level multifactorial analysis results, the goodness of fit identities of the scale were found at an acceptable level, with the following values: RMSEA 0.067; GFI 0.92; AGFI 0.87; CFI 0.95; andχ2 79.876 (P = .000). It was determined that the Anti-TNF Alpha Treatment Adherence Scale represents the area to be measured, measures the researched structure, has a high internal consistency between items, is interrelated, and is consistent over time. As a result of all mea- surements, it was determined that it is a valid and reliable scale.

Anti-TNF treatment in ankylosing spondylitis patients with chronic kidney disease: Is it effective and safe?

This study aims to examine the efficacy and safety of the antitumor necrosis factor (TNF) drugs in ankylosing spondylitis (AS) patients with chronic kidney disease. In this study, 24 male patients with a glomerular filtration rate (GFR) of <60 mL min􏰁1 1.73 m􏰁2 were included among 863 patients who were followed-up once in 3 months regularly from 2010 to 2018years. Twenty-four patients were chosen for the control group among 420 male patients whose renal functions were normal using random sampling. We examined C-reactive protein, erythro- cyte sedimentation rate, serum creatinine, and GFR values, and also the measurements of Bath Anky- losing Spondylitis Disease Activity Index (BASDAI) were recorded at the beginning of the treatment with anti-TNF agents and in the 3rd, 6th, 9th, 12th, and final visit months. Eleven (45.9%) of the patients included in the study were in the routine dialysis program. The initial anti-TNF treatments were etanercept (62.5%), infliximab (16.7%), adalimumab (16.7%), and goli- mumab (4.1%). Treatment was effective in 22 (91.7%) of the patients. When the values of the two groups' patients were compared at the beginning of the treatment, there was a substantial reduction regarding BASDAI (P < .001). Pleural effusion, infective endocarditis, septic arthritis, and prosthesis infection were major side effects (n 1⁄4 4). The mortality rate of the 24 patients was 29.2% (n 1⁄4 7). This study demonstrated that anti-TNF drug treatment is effective and safe in patients with AS who have chronic kidney disease.

OA15 Drivers of change in four and two component disease activity scores after etanercept treatment, in a multi-centre cohort of patients with established rheumatoid arthritis

Abstract Background/Aims Treatment response in RA is measured by different disease activity scores (DAS28). The widely used 4 component (4C) DAS28 does not always correlate with synovitis, and a new 2 component version (2C) DAS28 has been developed to address this problem. Here, we use multivariable linear regression models to identify drives of change (Δ) in 4C and 2C DAS28 after 3 months on the anti-TNF drug etanercept (ETN). Methods Using data from the Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS), we identified patients treated with originator or biosimilar ETN (N = 773). Differences between the follow-up (FU) and baseline (BL) DAS28, adjusted for baseline, serve as outcome variables. Multiple imputation by chained equations was used to impute missing data, and models were internally validated via bootstrapping. Table 1 shows the baseline statistics, and model parameters for the included covariates. Results We found that 15.8% (95% CI: 11 - 20.6%) of the variance in Δ4C was explained by the baseline DAS28, compared to 26.3% (95% CI: 20.9 - 31.7%) for the Δ2C. Age of onset, HAQ score and concurrent DMARD treatment were significantly associated with both ΔDAS28 scores. Δ4C-DAS28 was additionally associated with first biologic use, seropositivity for either rheumatoid factor or anti-citrullinated peptide antibodies, and the Hospital Anxiety and Depression Scale-Anxiety score. The only additional predictor significantly associated with Δ2C-DAS28 was weight. After adjusting for baseline DAS28, the additional clinical covariates only explained 7.6% (IQR: 7.3 - 7.8%), and 2.3% (IQR: 2.0 - 2.6%) of the variance for the 4C- and 2C-DAS28, respectively. Conclusion ΔDAS28 is heavily influenced by the baseline DAS28, and additional clinical covariates explain little to none of the additional variance. Notably, known factors associated with treatment response, such as seropositivity and previous unsuccessful treatments, were only significant for the 4C-DAS28. This suggests that the 4C DAS and 2C DAS capture different aspects of RA disease progression. Further association studies are required to find other reliable predictors for ΔDAS28, which may include biological markers of response. Significant covariates identified here should be considered as potential confounding factors. Disclosure M. Stadler: None. S. Ling: None. N. Nair: None. J. Isaacs: None. K. Hyrich: None. A. Morgan: None. G. Wilson: None. D. Plant: None. J. Bowes: None. A. Barton: None.

Dynamics of kidney disorders in children with juvenile idiopathic arthritis taking into account therapy resume

Introduction. In the study of the course and consequences of rheumatic diseases much attention is paid to comorbid conditions that significantly affect the function of internal organs, including kidneys. According to the concept of cardiorenal ratios, even minor renal impairment can be an independent risk factor for cardiovascular events and death. Objective. To determine the features of functional disorders of the kidneys in children and adolescents with juvenile idiopathic arthritis (JIA), taking into account the nature of the disease and therapy. Materials and methods. 85 children (8–18 years) with JIA, oligo- (61.5 %) and polyarthritis (38.5 %), 63 girls and 22 boys were examined. The average duration of the disease was 84.13 ± 6.28 months. The study was conducted twice with an interval of one year. Determination of renal status included studies of urinary sediment, concentration and nitrogen excretion capacity of the kidneys (fluctuations in specific weight during the day, daily proteinuria, creatinine and urea in the blood, glomerular filtration rate (GFR)). Statistical processing of the material was performed using parametric (Student's t-test (p), Fisher's angular transformation) and non-parametric parameters (Wilcoxon-Mann-Whitney), correlation and regression analysis. Results. Changes in renal function did not depend on the sex of patients and included proteinuria (9.09 %), namely microalbuminuria, which occurred in all variants of arthritis; reduction of GFR (8.26 %) – only in polyarthritis and uveitis-associated variants. Comparison of the frequency of renal changes in patients with varying degrees of disease activity showed their absence in the inactive stage of JIA. With active inflammatory process functional disorders of the kidneys occurred from 16.67 % to 26.32 % of cases, regardless of the degree of activity One year later there are positive changes: increased glomerular filtration rate (p ≤ 0.05), a tendency to decrease serum creatinine (p ≤ 0.1) on the background of basic methotrexate therapy up to 15 mg/m2/week. The combination of methotrexate therapy with the anti-TNF immunobiological drug (adalimumab) showed greater efficacy in improving renal function, a significant increase in GFR (p ≤ 0.05), a decrease in serum creatinine (p ≤ 0.05) and proteinuria (р ≤ 0,05). Conclusions. Children with JIA have changes in renal function, more often with uveitis-associated arthritis and methotrexate over 15 mg/m2/week. The inclusion of immunobiological drugs in the treatment not only reduces the activity of the disease, but also reduces the risk of concomitant comorbid lesions of internal organs, including kidneys.

Clinical settings with tofacitinib in ulcerative colitis.

There are aspects of Janus kinase (JAK) inhibitors, specifically tofacitinib, that distinguish them from other drugs used in the treatment of ulcerative colitis (UC), such as their oral administration, their short half-life and their lack of immunogenicity. With the available evidence, we can highlight tofacitinib's quick action and flexibility of use, and its efficacy in patients, irrespective of whether or not they have previously been exposed to TNF inhibitors (anti-TNF drugs) and other biologic agents. Moreover, their safety profile is known and manageable, with certain considerations and precautions being factored in before and during treatment. In this review, we have defined various scenarios pertaining to this drug, e.g. its use in the event of failure or intolerance to previous treatment with biologics, when a quick response is required or in patients with other concurrent immune-mediated diseases.

Dual Biologic Therapy for the Treatment of Pediatric Inflammatory Bowel Disease: A Review of the Literature.

Background: pediatric patients with inflammatory bowel diseases (IBD) who qualify for biological therapy represent a group of severely ill patients. They have never been successful with conventional medication. Biologic medications in monotherapy are frequently used in the disease course, however they result in a 1-year remission, which can be maintained in approximately 40% of IBD patients. Method: the present study aims to summarize the review of literature data on the use of therapy with a combination of two biological and small molecule drugs, anti-TNF (infliximab, adalimumab), vedolizumab and ustekinumab, as well as Janus kinase inhibitors (tofacitinib). The risks associated with the use of dual biological therapy and potential adverse effects are particularly important. The literature data was reviewed using the following terms: “use of combination biologic in paediatric IBD”, “combination biologics”, and “dual biologic for treatment of Inflammatory Bowel Disease”. Conclusion: the use of dual biological therapy is a new therapeutic option. In pediatric IBD, combining the different mechanisms of action of the two biological drugs seems to be safe and effective. Anti-TNF drugs with vedolizumab or ustekinumab may be a particularly beneficial combination. Nevertheless, the clarification and justification of potential advantages of combined biological therapies in further studies, such as randomized control trials, are needed.

Uncovering Novel Pre-Treatment Molecular Biomarkers for Anti-TNF Therapeutic Response in Patients with Crohn's Disease.

Neutralising monoclonal antibodies for tumour necrosis factor (TNF) has been widely used to treat Crohn’s disease (CD) in clinical practice. However, differential individual response necessitates a therapeutic response assessment of anti-TNF agents in CD patients for optimizing therapeutic strategy. We aimed to predict anti-TNF therapy response in CD patients using transcriptome analyses. Transcriptome analyses were performed using data from the Gene Expression Omnibus, GeneCards, and Human Protein Atlas databases. The significantly mitigated biological functions associated with anti-TNF therapy resistance in CD patients encompassed immune pathways, including Interleukin-17 (IL-17) signaling, cytokine-cytokine receptor interaction, and rheumatoid arthritis. The scores of immune cell markers, including neutrophils, monocytes, and macrophages/monocytes were also significantly decreased in non-responders compared with that measured in anti-TNF therapy responders. The KAT2B gene, associated with IL-17 cytokine mediated neutrophil mobilization and activation, was significantly under-expressed in both tissue and peripheral blood mononuclear cells (PBMCs) in anti-TNF therapy-resistant CD patients. The reduced expression of several pro-inflammatory cytokines due to down-regulated IL-17 signaling, is suggestive of the primary non-response to anti-TNF agents in CD patients. Furthermore, the PBMC KAT2B gene signature may be a promising pre-treatment prognostic biomarker for anti-TNF drug response in CD patients.

Therapeutic Drug Monitoring in Perianal Fistulizing Crohn’s Disease

Perianal fistulas are a common complication of Crohn’s disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn’s disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is an important unmet need. Given its emerging role in other phenotypes of Crohn’s disease, the use of TDM could also offer an opportunity to enhance the effectiveness of available therapies and improve outcomes in the subset of patients with PFCD receiving biologics. Overall, there is mounting evidence that higher anti-TNF drug levels are associated with better rates of “fistula healing”. However, studies have been limited by their use of subjective outcomes and observational designs. Ultimately, further interventional, randomized controlled trials looking into the relationship between drug exposure and fistula outcomes are needed.

The Impact of Intermediate Antidrug Antibodies to Infliximab and Adalimumab on Clinical Outcomes in Patients with Crohn’s Disease or Ulcerative Colitis

Background: The anti-TNF drugs adalimumab (ADA) and infliximab (IFX) are effective treatments for inflammatory bowel disease (IBD). However, 40% of patients lose response, often due to the development of antibodies-to-ADA (ATA) and antibodies-to-IFX (ATI). While low ATA/ATI titres (&lt;200 ng/mL) are associated with better outcomes and high ATA/ATI titres (&gt;1,000 ng/mL) are associated with poorer outcomes, the significance of intermediate ATA/ATI titres (200–999 ng/mL) is not well understood. This study aims to investigate the impact of intermediate ATA/ATI titres on outcomes in patients with IBD. Methods: A retrospective chart review of 376 patients with IBD was conducted. The primary clinical outcome was persistence on anti-TNF therapy for 1 year after the measurement of ATA/ATI titres. The participants consisted of patients with IBD treated with IFX or ADA at the University of Maryland Medical Center’s Inflammatory Bowel Disease Program between October 2016 and October 2019. Results: Out of 322 patients with low titres, 271 persisted on their original anti-TNF, compared with nine out the 15 patients with intermediate titres (p=0.026) and one out the 10 patients with high titres (p&lt;0.0001). The odds ratio of persistence when comparing intermediate titres to low titres was 0.26 (0.09–0.80), and when comparing high titres to low titres was 0.02 (0.00–0.14). Conclusion: Patients with intermediate titres were more likely to lose response to anti-TNF drugs and require a change in anti-TNF therapy than patients with low titres. Although the sample size of patients with intermediate titres was small, providers should consider dose optimisation of anti-TNF drugs, with or without the addition of an immunosuppressant, when intermediate titres are present.